Method and reagent for the treatment of Alzheimer&#39;s disease

ABSTRACT

Nucleic acid molecules, including antisense and enzymatic nucleic acid molecules, such as hammerhead ribozymes, DNAzymes, allozymes (allosteric ribozymes, aptazymes) and antisense, which modulate and/or detect the expression of molecular targets impacting the development and progression of Alzheimer&#39;s disease, in particular, the expression of beta secretase (BACE), presenilin- 2  (ps- 2 ), and amyloid precursor protein (APP) genes.

[0001] This patent application is a continuation-in-part of Blatt etal., U.S. Ser. No. 09/745,237, filed Dec. 20, 2000, entitled “METHOD ANDREAGENT FOR THE TREATMENT OF ALZHEIMER'S DISEASE” which claims thebenefit of Blatt et al., U.S. provisional application serial No.60/173,612, filed Dec. 29, 1999, entitled “METHOD AND REAGENT FOR THETREATMENT OF ALZHEIMER'S DISEASE” These applications are herebyincorporated by reference herein in their entirety including thedrawings.

BACKGROUND OF THE INVENTION

[0002] The present invention concerns compounds, compositions, andmethods for the study, diagnosis, and treatment of Alzheimer's disease(AD).

[0003] The following is a brief description of the current understandingof Alzheimer's disease. The discussion is not meant to be complete andis provided only to assist understanding the invention that follows. Thesummary is not an admission that any of the work described below isprior art to the claimed invention.

[0004] Alzheimer's disease (AD) is a progressive, degenerative diseaseof the brain which affects approximately 4 million people in the UnitedStates alone. An estimated 14 million Americans will have Alzheimer'sdisease by the middle of the next century if no cure or definitiveprevention of the disease is found. Nearly one out of ten people overage 65 and nearly half of those over 85 have Alzheimer's disease.Alzheimer's disease is not confined to the elderly, a small percentageof people in their 30's and 40's are afflicted with early onset AD.Alzheimer's disease is the most common form of dementia, and amounts tothe third most expensive disease in the US following heart disease andcancer. An estimated 100 billion dollars are spent annually onAlzheimer's disease (National Alzheimer's Association, 1999).

[0005] Alzheimer's disease is characterized by the progressive formationof insoluble plaques and vascular deposits in the brain consisting ofthe 4 kD amyloid P peptide (Aβ). These plaques are characterized bydystrophic neurites that show profound synaptic loss, neurofibrillarytangle formation, and gliosis. Aβ arises from the proteolytic cleavageof the large type I transmembrane protein, β-amyloid precursor protein(APP) (Kang et al., 1987, Nature, 325, 733). Processing of APP togenerate Aβ requires two sites of cleavage by a β-secretase and aγ-secretase. β-secretase cleavage of APP results in the cytoplasmicrelease of a 100 kD soluble amino-terminal fragment, APPsβ, leavingbehind a 12 kD transmembrane carboxy-terminal fragment, C99.Alternately, APP can be cleaved by a α-secretase to generate cytoplasmicAPPsα and transmembrane C83 fragments. Both remaining transmembranefragments, C99 and C83, can be further cleaved by a γ-secretase, leadingto the release and secretion of Alzheimer's related Aβ and anon-pathogenic peptide, p3, respectively (Vassar et al., 1999, Science,286, 735-741). Early onset familial Alzheimer's disease is characterizedby mutant APP protein with a Met to Leu substitution at position P1,characterized as the “Swedish” familial mutation (Mullan et al., 1992,Nature Genet., 1, 345). This APP mutation is characterized by a dramaticenhancement in β-secretase cleavage (Citron et al., 1992, Nature, 360,672).

[0006] The identification of β-secretase, and γ-secretase constituentsinvolved in the release of β-amyloid protein is of primary importance inthe development of treatment strategies for Alzheimer's disease.Characterization of α-secretase is also important in this regard sinceα-secretase cleavage may compete with β-secretase cleavage resulting innon-pathogenic vs. pathogenic protein production. Involvement of the twometalloproteases, ADAM 10, and TACE has been demonstrated in α-cleavageof AAP (Buxbaum et al., 1999, J Biol. Chem., 273, 27765, and Lammich etal., 1999, Proc. Natl. Acad. Sci. U.S.A., 96, 3922). Studies ofγ-secretase activity have demonstrated presenilin dependence (De Stooperet al., 1998, Nature, 391, 387, and De Stooper et al., 1999, Nature,398, 518), and as such, presenilins have been proposed as γ-secretaseeven though presenilin does not present proteolytic activity (Wolfe etal., 1999, Nature, 398, 513).

[0007] Recently, Vassar et al., 1999, supra reported β-secretasecleavage of AAP by the transmembrane aspartic protease beta site APPcleaving enzyme, BACE. While other potential candidates for β-secretasehave been proposed (for review see Evin et al., 1999, Proc. Natl. Acad.Sci. U.S.A., 96, 3922), none have demonstrated the full range ofcharacteristics expected from this enzyme. Vassar et al, supra,demonstrate that BACE expression and localization are as expected forβ-secretase, that BACE overexpression in cells results in increasedβ-secretase cleavage of APP and Swedish APP, that isolated BACEdemonstrates site specific proteolytic activity on APP derived peptidesubstrates, and that antisense mediated endogenous BACE inhibitionresults in dramatically reduced β-secretase activity.

[0008] Current treatment strategies for Alzheimer's disease rely oneither the prevention or the alleviation of symptoms and/or the slowingdown of disease progression. Two drugs approved in the treatment ofAlzheimer's, donepezil (Aricept®) and tacrine (Cognex®), bothcholinomimetics, attempt to slow the loss of cognitive ability byincreasing the amount of acetylcholine available to the brain.Antioxidant therapy through the use of antioxidant compounds such asalpha-tocopherol (vitamin E), melatonin, and selegeline (Eldepryl®)attempt to slow disease progression by minimizing free radical damage.Estrogen replacement therapy is thought to incur a possible preventativebenefit in the development of Alzheimer's disease based on limited data.The use of anti-inflammatory drugs may be associated with a reduced riskof Alzheimer's as well. Calcium channel blockers such as Nimodipine® areconsidered to have a potential benefit in treating Alzheimer's diseasedue to protection of nerve cells from calcium overload, therebyprolonging nerve cell survival. Nootropic compounds, such asacetyl-L-carnitine (Alcar®) and insulin, have been proposed to have somebenefit in treating Alzheimer's due to enhancement of cognitive andmemory function based on cellular metabolism.

[0009] Whereby the above treatment strategies may all improve quality oflife in Alzheimer's patients, there exists an unmet need in thecomprehensive treatment and prevention of this disease. As such, thereexists the need for therapeutics effective in reversing thephysiological changes associated with Alzheimer's disease, specifically,therapeutics that can eliminate and/or reverse the deposition of amyloidβ peptide. The use of compounds to modulate the expression of proteasesthat are instrumental in the release of amyloid β peptide, namelyβ-secretase (BACE), and γ-secretase (presenilin), is of therapeuticsignificance.

[0010] Tsai et al., 1999, Book of Abstrasts, 218^(th) ACS NationalMeeting, New Orleans, August 22-26, describes substrate-basedalpha-aminoisobutyric acid derivatives of difluoro ketone peptidomimeticinhibitors of amyloid β peptide through γ-secretase inhibition.

[0011] Czech et al., International PCT publication No. WO 99/21886,describes peptides capable of inhibiting the interaction betweenpresenilins and the β-amyloid peptide or its precursor for therapeuticuse.

[0012] Fournier et al., International PCT publication No. WO 99/16874,describes human brain proteins capable of interacting with presenilinsand cDNAs encoding them toward therapeutic use.

[0013] St. George-Hyslop et al., International PCT publication No. WO97/27296, describes genes for proteins that interact with presenilinsand their role in Alzheimer's disease toward therapeutic use.

[0014] Vassar et al., 1999, Science, 286, 735-741, describes specificantisense oligonucleotides targeting BACE, used for inhibition studiesof endogenous BACE expression in 101 cells and APPsw cells via lipidmediated transfection.

[0015] Fechteler et al., International PCT publication No. WO 00/03004,describes specific hammerhead ribozymes targeting presenilin-2 RNA.

[0016] Denman, 2000, Mol. Cell Biol. Res. Commun., 4, 239-247; and VanLeeuwen, International PCT publication No. WO 98/45322, describespecific ribozymes targeting beta-amyloid precursor protein.

SUMMARY OF THE INVENTION

[0017] The invention features novel nucleic acid-based techniques (e.g.,enzymatic nucleic acid molecules, for example ribozymes, decoys, and RNAinterference, for example double stranded RNA “dsRNA” such as shortinterfering RNA, “siRNA”), and methods for their use to modulate theexpression of molecular targets impacting the development andprogression of Alzheimer's disease. The invention also features nucleicacid sensor molecules whose activity is modulated by Alzheimer's relatedproteins, peptides, RNA or DNA, for example beta-amyloid proteins orpeptides; beta-secretase (BACE) proteins, peptides, RNA or DNA;presenilin-2 (ps-2) proteins, peptides, RNA or DNA; or amyloid precursorprotein (APP) proteins, peptides, RNA or DNA. Specifically, the presentinvention features nucleic acid sensor molecules for the diagnosis andtreatment of Alzheimer's disease.

[0018] In one embodiment, the invention features use of such novelnucleic acid-based techniques, independently or in combination, tomodulate, down regulate, or inhibit the expression of beta secretase,such as beta-site APP-cleaving enzyme (BACE, also known as Asp-2)(GenBank accession AF190725), and gamma secretase, such as presenilin 2(ps-2) (e.g., GenBank accession L43964) involved in cleavingbeta-amyloid precursor protein to yield amyloid β peptide.

[0019] In another embodiment, the invention features use of such novelnucleic acid based techniques, independently or in combination, tomodulate, down regulate, or inhibit the expression of presenilin 1(ps-1), for example GenBank accession No. L76517.

[0020] In another embodiment, the invention features use of such novelnucleic acid-based techniques, independently or in combination, tomodulate, down regulate, or inhibit the expression of amyloid precursorprotein, for example GenBank accession No. M33112.

[0021] In one embodiment, the invention features a nucleic acid sensormolecule capable of modulating the expression of beta-secretase, forexample BACE, in the presence of beta-amyloid protein.

[0022] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of gamma-secretase,for example presenilin-2, in the presence of beta-amyloid protein.

[0023] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of amyloidprecursor protein (APP), for example GenBank accession No. M33112, inthe presence of beta-amyloid protein.

[0024] In one embodiment, the invention features a nucleic acid sensormolecule capable of modulating the expression of beta-secretase, forexample BACE, in the presence of amyloid precursor protein.

[0025] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of gamma-secretase,for example presenilin-2, in the presence of amyloid precursor protein.

[0026] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of amyloidprecursor protein (APP), for example GenBank accession No. M33112, inthe presence of amyloid precursor protein.

[0027] In one embodiment, the invention features a nucleic acid sensormolecule capable of modulating the expression of beta-secretase, forexample BACE, in the presence of beta-secretase RNA.

[0028] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of gamma-secretase,for example presenilin-2, in the presence of beta-secretase RNA.

[0029] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of amyloidprecursor protein (APP), for example GenBank accession No. M33112, inthe presence of beta-secretase RNA.

[0030] In one embodiment, the invention features a nucleic acid sensormolecule capable of modulating the expression of beta-secretase, forexample BACE, in the presence of gamma-secretase RNA.

[0031] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of gamma-secretase,for example presenilin-2, in the presence of gamma-secretase RNA.

[0032] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of amyloidprecursor protein (APP), for example GenBank accession No. M33112, inthe presence of gamma-secretase RNA.

[0033] In one embodiment, the invention features a nucleic acid sensormolecule capable of modulating the expression of beta-secretase, forexample BACE, in the presence of amyloid precursor protein (APP) RNA.

[0034] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of gamma-secretase,for example presenilin-2, in the presence of amyloid precursor protein(APP) RNA.

[0035] In another embodiment, the invention features a nucleic acidsensor molecule capable of modulating the expression of amyloidprecursor protein (APP), for example GenBank accession No. M33112, inthe presence of amyloid precursor protein (APP) RNA.

[0036] In one embodiment, the nucleic acid sensor molecule of theinvention is a half zyme.

[0037] In another embodiment, the invention features the use of anenzymatic nucleic acid molecule, preferably in the hammerhead, NCH,G-cleaver, hairpin, Zinzyme, Amberzyme and/or DNAzyme motif, to inhibitthe expression of beta-site APP-cleaving enzyme (BACE) gene, amyloidprecursor protein (APP) gene, and/or the presenilin-2 (ps-2) gene.

[0038] The present invention also relates to nucleic acid-basedmolecular sensors whose activity can be modulated by the presence orabsence of various signaling agents, ligands, and/or target signalingmolecules associated with Alzheimer's disease. The invention furtherrelates to a method for the detection of specific target signalingmolecules such as nucleic acid molecules, proteins, peptides,antibodies, polysaccharides, lipids, sugars, metals, microbial orcellular metabolites, analytes, pharmaceuticals, and other organic andinorganic molecules related to Alzheimer's disease, by using nucleicacid sensor molecules of the invention in a variety of settings,including clinical, genomic, and research applications. The inventionfurther relates to the use of the nucleic acid sensor molecule asmolecular sensors capable of modulating the activity, function, orphysical properties of other molecules, for example molecules associatedwith Alzheimer's disease. The present invention also contemplates theuse of the nucleic acid sensor molecule constructs as molecularswitches, capable of inducing or negating a response to or againstAlzheimer's disease in a system, for example in biological system.

[0039] The invention further relates to the use of nucleic acid sensormolecules in a diagnostic application to identify the presence of atarget signaling molecule such as a gene and/or gene products which areindicative of a particular genotype and/or phenotype, for example, thepresence or absence of gene expression associated with Alzheimer'sdisease, within patients or patient samples. The invention also relatesto a method for the diagnosis of disease states or physiologicalabnormalities related to the expression of RNA and DNA related to themaintenance or progression of Alzheimer's disease.

[0040] Diagnostic applications of the nucleic acid sensor moleculesinclude the use of the nucleic acid sensor molecules for prospectivediagnosis of neurological diseases including Alzheimer's disease,prognosis of therapeutic effect and/or dosing of a drug or class ofdrugs related to the treatment of neurological diseases, prognosis andmonitoring of neurological disease outcome, monitoring of patientprogress as a function of an approved drug or a drug under developmentfor the treatment of neurological diseases such as Alzheimer's disease,patient surveillance and screening for drug and/or drug treatments forneurological diseases. Diagnostic applications include the use ofnucleic acid sensors for research, development and commercialization ofproducts for the rapid detection of macromolecules, such as moleculesrelated to the maintenance or progression of neurological diseases suchas Alzheimer's disease.

[0041] Nucleic acid sensor molecules can also be used in assays toassess the specificity, toxicity and effectiveness of various smallmolecules, nucleoside analogs, or non-nucleic acid drugs, or doses of aspecific small molecules, nucleoside analogs or nucleic acid andnon-nucleic acid drugs, against validated targets or biochemicalpathways associated with neurological diseases such as Alzheimer'sdisease, and include the use of nucleic acid sensors in assays involvedin high-throughput screening, biochemical assays, including cellularassays, in vivo animal models, clinical trial management, and formechanistic studies in human clinical studies related to neurologicaldiseases such as Alzheimer's disease.

[0042] In one embodiment, the nucleic acid sensor molecule of theinvention comprises an enzymatic nucleic acid component and one or moresensor components, wherein, in response to an interaction of a targetsignaling molecule, for example BACE, ps-2, or APP, with the nucleicacid sensor molecule, the enzymatic nucleic acid component catalyzes achemical reaction; such as covalent attachment of at least a portion ofa reporter molecule to the nucleic acid sensor molecule, or cleavage ofa reporter molecule.

[0043] In another embodiment, the invention features a method,comprising the steps of: (a) contacting a nucleic acid sensor moleculecomprising an enzymatic nucleic acid component and one or more sensorcomponents, in which the enzymatic nucleic acid component catalyzes achemical reaction in response to an interaction between a targetsignaling molecule, for example BACE, ps-2, or APP, and the nucleic acidsensor molecule, with a system under conditions suitable for theenzymatic nucleic acid component to catalyze a chemical reactioninvolving the attachment of at least a portion of a reporter molecule tothe nucleic acid sensor molecule in the presence of a target signalingagent; and (b) assaying for the attachment of the reporter molecule tothe nucleic acid sensor molecule.

[0044] In another embodiment, the invention features a method,comprising the steps of: (a) contacting a nucleic acid sensor moleculecomprising an enzymatic nucleic acid component and one or more sensorcomponents, in which the enzymatic nucleic acid component catalyzes achemical reaction in response to an interaction between a targetsignaling molecule, for example BACE, ps-2, or APP, and the nucleic acidsensor molecule, with a system under conditions suitable for theenzymatic nucleic acid component to catalyze a chemical reactioninvolving the cleavage of at least a portion of a reporter molecule, forexample a molecular beacon, in the presence of a target signaling agent;and (b) assaying for the cleavage of the reporter molecule.

[0045] In another embodiment, the invention features a method,comprising the steps of: (a) contacting a nucleic acid sensor moleculecomprising an enzymatic nucleic acid component and one or more sensorcomponents, in which the enzymatic nucleic acid component catalyzes achemical reaction in response to an interaction between a targetsignaling molecule, for example BACE, ps-2, or APP, and the nucleic acidsensor molecule, with a system under conditions suitable for theenzymatic nucleic acid component to catalyze a chemical reactioninvolving the cleavage of at least a portion of a reporter molecule fromthe nucleic acid sensor molecule in the presence of a target signalingagent; and (b) assaying for the cleavage of the reporter molecule fromthe nucleic acid sensor molecule.

[0046] In another embodiment, the invention features a method,comprising the steps of: (a) contacting a nucleic acid sensor moleculecomprising an enzymatic nucleic acid component and one or more sensorcomponents, in which the enzymatic nucleic acid component catalyzes achemical reaction in response to an interaction between a targetsignaling molecule, for example BACE, ps-2, or APP, and the nucleic acidsensor molecule, with a system under conditions suitable for theenzymatic nucleic acid component to catalyze a chemical reactioninvolving the cleavage of at least a portion of a reporter molecule thatis attached to a solid support in the presence of a target signalingagent; and (b) assaying for the cleavage of the reporter molecule fromthe solid support.

[0047] In one embodiment, the nucleic acid sensor molecule of theinstant invention features an enzymatic component and a sensor componentthat are distinct moieties.

[0048] In another embodiment, the nucleic acid sensor molecule of theinstant invention features a linker region that joins a sensor componentto an enzymatic nucleic acid component.

[0049] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of atarget signaling molecule with the nucleic acid sensor molecule, theenzymatic nucleic acid component catalyzes a chemical reaction involvingcovalent attachment of at least a portion of a reporter molecule to atleast a portion of the nucleic acid sensor molecule, wherein thereporter molecule comprises the formula:

R₁—L—R₂

[0050] wherein R1 is selected from the group consisting of alkyl,alkoxy, hydrogen, hydroxy, sulfhydryl, ester, anhydride, acid halide,amide, nitrile, phosphate, phosphonate, nucleoside, nucleotide,oligonucleotide; R2 is selected from the group consisting of molecularbeacons, small molecules, fluorophores, chemophores, ionophores,radio-isotopes, photophores, peptides, proteins, enzymes, antibodies,nucleic acids, and enzymatic nucleic acids; L represents a linker whichcan be present or absent, and “—” represents a chemical bond.

[0051] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of atarget signaling molecule with the nucleic acid sensor molecule, theenzymatic nucleic acid component catalyzes a chemical reaction involvingcleavage of at least a portion of a reporter molecule, wherein thereporter molecule comprises the formula:

R₁—L—R₂

[0052] wherein R1 is selected from the group consisting of alkyl,alkoxy, hydrogen, hydroxy, sulfhydryl, ester, anhydride, acid halide,amide, nitrile, phosphate, phosphonate, nucleoside, nucleotide,oligonucleotide; R2 is selected from the group consisting of molecularbeacons, small molecules, fluorophores, chemophores, ionophores,radio-isotopes, photophores, peptides, proteins, enzymes, antibodies,nucleic acids, and enzymatic nucleic acids; L represents a linker whichcan be present or absent, and “—” represents a chemical bond.

[0053] In one embodiment, the detection of a chemical reaction catalyzedby a nucleic acid sensor molecule of the instant invention is indicativeof the presence of the target signaling molecule in a system.

[0054] In another embodiment, the absence of a chemical reactioncatalyzed by a nucleic acid sensor molecule of the instant invention isindicative of a system lacking the target signaling molecule.

[0055] In another embodiment, the invention features a method comprisingthe steps of: (a) contacting a nucleic acid sensor molecule whichcomprises (i) an enzymatic nucleic acid component comprising a substratebinding region and a catalytic region; and (ii) a sensor componentcomprising a nucleic acid sequence that upon interacting with acomplementary sequence in the enzymatic nucleic acid component, inhibitsthe activity of the enzymatic nucleic acid component, and a reportermolecule comprising a nucleic acid sequence complementary to thesubstrate binding region of the enzymatic nucleic acid component of thenucleic acid sensor molecule, with a system under conditions suitablefor the enzymatic nucleic acid component of the nucleic acid sensormolecule to catalyze cleavage of the reporter molecule in the presenceof a target signaling molecule; and (b) assaying for the cleavagereaction of step (a).

[0056] In another embodiment, the invention features a method comprisingthe steps of: (a) contacting a nucleic acid sensor molecule whichcomprises (i) an enzymatic nucleic acid component comprising a substratebinding region and a catalytic region; and (ii) a sensor componentcomprising a nucleic acid sequence that upon interacting with acomplementary sequence in the enzymatic nucleic acid component inhibitsthe activity of the enzymatic nucleic acid component and a reportermolecule comprising a nucleic acid sequence complementary to thesubstrate binding region of the enzymatic nucleic acid component of thenucleic acid sensor molecule, with a system under conditions suitablefor the enzymatic nucleic acid component of the nucleic acid sensormolecule to catalyze a ligation reaction involving the reporter moleculein the presence of a target signaling molecule, and (b) assaying for theligation reaction in step (a).

[0057] In one embodiment of the inventive method, the ligation reactioncatalyzed by the nucleic acid sensor molecule causes at least a portionof a reporter molecule to be attached to the nucleic acid sensormolecule.

[0058] In another embodiment, the ligation reaction catalyzed by thenucleic acid sensor molecule causes at least a portion of a reportermolecule to be attached to a separate molecule. Suitable moleculesinclude, for example, a separate nucleic acid molecule, peptide,protein, small molecule, biotin, or surface.

[0059] Also, in one embodiment of the inventive method, the cleavage ofa reporter molecule catalyzed by the nucleic acid sensor molecule isindicative of the presence of the target signaling molecule in thesystem. In another embodiment, the absence of cleavage of a reportermolecule catalyzed by the nucleic acid sensor molecule is indicative ofthe system lacking the target signaling molecule.

[0060] In another embodiment of the inventive method, the ligation of areporter molecule catalyzed by the nucleic acid sensor molecule isindicative of the presence of the target signaling molecule in thesystem. In another embodiment, the absence of ligation of a reportermolecule catalyzed by the nucleic acid sensor molecule is indicative ofthe system lacking the target signaling molecule.

[0061] In one embodiment, the system of the instant invention is an invitro system. Preferably, the in vitro system is a sample derived fromthe group consisting of a patient, plant, water, beverage, and foodpreparation.

[0062] In one embodiment, the target signaling molecule of the instantinvention is an RNA, DNA, analog of RNA or analog of DNA. Preferably,the target signaling molecule of the instant invention is an RNA derivedfrom a bacteria, virus, fungi, plant or mammalian genome.

[0063] In one embodiment, the enzymatic nucleic acid component of thenucleic acid sensor molecule is selected from the group consisting ofhammerhead, hairpin, inozyme, G-cleaver, Zinzyme, RNase P EGS nucleicacid and Amberzyme motif. In another embodiment, the enzymatic nucleicacid component of the nucleic acid sensor molecule is a DNAzyme.

[0064] In one embodiment, the reporter molecule of the instant inventioncomprises a detectable label selected from the group consisting ofchromogenic substrate, fluorescent labels, chemiluminescent labels, andradioactive labels and enzymes. Suitable enzymes include, for example,luciferase, horseradish peroxidase, and alkaline phosphatase.

[0065] In another embodiment, the reporter molecule of the instantinvention is immobilized on a solid support. Suitable solid supportsinclude silicon-based chips, silicon-based beads, controlled pore glass,polystyrene, cross-linked polystyrene, nitrocellulose, biotin, plastics,metals and polyethylene films.

[0066] In one embodiment the sensor component of the nucleic acid sensormolecule is RNA, DNA, analog of RNA or analog of DNA.

[0067] In another embodiment, the sensor component of the nucleic acidsensor molecule is covalently linked to the nucleic acid sensor moleculeby a linker. Suitable linkers include one or more nucleotides, abasicmoieties, polyethers, polyamines, polyamides, peptides, carbohydrates,lipids, and polyhydrocarbon compounds, and any combination thereof.

[0068] In another embodiment, the sensor component of the nucleic acidsensor molecule is not covalently linked to the nucleic acid sensormolecule.

[0069] In another embodiment, the reporter molecule of the instantinvention is RNA, DNA, RNA analog, or DNA analog.

[0070] In another embodiment, the invention features a kit comprising:(a) a nucleic acid sensor molecule which comprises (i) an enzymaticnucleic acid component comprising a substrate binding region and acatalytic region; and (ii) a sensor component comprising a nucleic acidwhich interacts with a complementary sequence in the enzymatic nucleicacid component to inhibit the activity of the enzymatic nucleic acidcomponent; and (b) a reporter molecule that can be modified, i.e.,cleaved, ligated, polymerized, isomerized, phorphorylated, and/ordephosphorylated by the enzymatic nucleic acid component of the nucleicacid sensor molecule in the presence of a target signaling molecule, forexample BACE, ps-2, or APP, wherein the reporter molecule comprises achemical moiety capable of emitting a detectable signal upon itsmodification.

[0071] In another embodiment, the invention features a kit whichcomprises: (a) a nucleic acid sensor molecule comprising an enzymaticnucleic acid component and one or more sensor components; and (b) areporter molecule, wherein, in response to an interaction of a targetsignaling molecule, for example BACE, ps-2, or APP, with the nucleicacid sensor molecule, the enzymatic nucleic acid component catalyzes achemical reaction involving covalent attachment of at least a portion ofa reporter molecule to the nucleic acid sensor molecule.

[0072] In another embodiment, the invention features a kit whichcomprises: (a) a nucleic acid sensor molecule comprising, an enzymaticnucleic acid component and one or more sensor components; and (b) areporter molecule, wherein in response to an interaction of a targetsignaling molecule, for example BACE, ps-2, or APP, with the nucleicacid sensor molecule, the enzymatic nucleic acid component is capable ofcarrying out a chemical reaction involving isomerization of at least aportion of a reporter molecule.

[0073] In another embodiment, the invention features a kit whichcomprises: (a) a nucleic acid sensor molecule comprising an enzymaticnucleic acid component and one or more sensor components; and (b) areporter molecule having a non-oligonucleotide-based portion, wherein,in response to an interaction of a target signaling molecule, forexample BACE, ps-2, or APP, with the nucleic acid sensor molecule, theenzymatic component catalyses a chemical reaction involvingphosphorylation of a non-oligonucleotide-based portion of a reportermolecule.

[0074] In another embodiment, the invention features a kit whichcomprises: (a) a nucleic acid sensor molecule comprising an enzymaticnucleic acid component and one or more sensor components; and (b) areporter molecule having a non-oligonucleotide-based portion, wherein,in response to an interaction of a target signaling molecule, forexample BACE, ps-2, or APP, with the nucleic acid sensor molecule, theenzymatic component catalyses a chemical reaction involvingdephosphorylation of a non-oligonucleotide-based portion of a reportermolecule.

[0075] In another embodiment, the invention features a method comprisingthe step of contacting one or more components of a kit of the instantinvention with a system under conditions suitable for the reportermolecule in the kit to be cleaved by the nucleic acid sensor molecule inthe kit in the presence of a target signaling molecule, for exampleBACE, ps-2, or APP.

[0076] In another embodiment, the invention features a method comprisingthe step of contacting one or more components of a kit of the instantinvention with a system under conditions suitable for at least a portionof the reporter molecule in the kit to be covalently attached to thenucleic acid sensor molecule in the kit in the presence of a targetsignaling molecule, for example BACE, ps-2, or APP.

[0077] In one embodiment, the invention features a method for isolatinga nucleic acid sensor molecule of the instant invention, comprising thesteps of: (a) contacting a random pool of nucleic acids with a targetsignaling molecule and a reporter molecule, and (b) isolating a nucleicacid sensor molecule that can catalyze a chemical reaction involvingcovalent attachment of at least a portion of the reporter molecule tothe nucleic acid sensor molecule in the presence of the target signalingmolecule, for example BACE, ps-2, or APP.

[0078] In another embodiment, the invention features a method forisolating a nucleic acid sensor molecule of the instant inventioncomprising the steps of: (a) contacting a random pool of nucleic acidswith a target signaling molecule and a reporter molecule, and (b)isolating a nucleic acid sensor molecule that can catalyze a chemicalreaction involving ligation of at least a portion of the reportermolecule to the nucleic acid sensor molecule in the presence of thetarget signaling molecule, for example BACE, ps-2, or APP.

[0079] In another embodiment, the invention features a method forisolating a nucleic acid sensor molecule of the instant inventioncomprising the steps of: (a) contacting a random pool of nucleic acidswith a target signaling molecule and a non-oligonucleotide-basedreporter molecule, and (b) isolating a nucleic acid sensor molecule thatcan catalyze a chemical reaction involving phosphorylation anon-oligonucleotide-based portion of the reporter molecule by thenucleic acid sensor molecule in the presence of the target signalingmolecule, for example BACE, ps-2, or APP.

[0080] In another embodiment, the invention features a method forisolating a nucleic acid sensor molecule of the instant invention,comprising the steps of: (a) contacting a random pool of nucleic acidswith a target signaling molecule and a non-oligonucleotide-basedreporter molecule, and (b) isolating a nucleic acid sensor molecule thatcan catalyze a chemical reaction involving dephosphorylation of anon-oligonucleotide-based portion of the reporter molecule by thenucleic acid sensor molecule in the presence of the target signalingmolecule, for example BACE, ps-2, or APP.

[0081] In one embodiment, the invention features a nucleic acid sensormolecule comprising an enzymatic nucleic acid component and one or moresensor components, wherein, in response to an interaction of a singlestranded RNA (ssRNA) having a SNP, for example a ssRNA related to themaintenance or progression of Alzheimer's disease, with the nucleic acidsensor molecule in a system, the enzymatic nucleic acid componentcatalyzes a chemical reaction resulting in a detectable response.

[0082] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of asingle stranded DNA (ssDNA) having a SNP, for example a ssDNA related tothe maintenance or progression of Alzheimer's disease, with the nucleicacid sensor molecule in a system, the enzymatic nucleic acid componentcatalyzes a chemical reaction resulting in a detectable response.

[0083] In yet another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of apeptide, for example a peptide related to the maintenance or progressionof Alzheimer's disease, with the nucleic acid sensor molecule in asystem, the enzymatic nucleic acid component catalyzes a chemicalreaction resulting in a detectable response.

[0084] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of aprotein, for example a protein related to the maintenance or progressionof Alzheimer's disease, with the nucleic acid sensor molecule in asystem, the enzymatic nucleic acid component catalyzes a chemicalreaction resulting in a detectable response.

[0085] In one embodiment, the invention features a nucleic acid sensormolecule comprising an enzymatic nucleic acid component and one or moresensor components, wherein, in response to an interaction of a singlestranded RNA (ssRNA), for example a ssRNA related to the maintenance orprogression of Alzheimer's disease, with the nucleic acid sensormolecule in a system, the enzymatic nucleic acid component catalyzes achemical reaction resulting in the cleavage of a predetermined RNAmolecule associated with a disease.

[0086] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of asingle stranded DNA (ssDNA), for example a ssDNA related to themaintenance or progression of Alzheimer's disease, with the nucleic acidsensor molecule in a system, the enzymatic nucleic acid componentcatalyzes a chemical reaction resulting in the cleavage of apredetermined RNA molecule associated with a disease.

[0087] In yet another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of apeptide, for example a peptide related to the maintenance or progressionof Alzheimer's disease, with the nucleic acid sensor molecule in asystem, the enzymatic nucleic acid component catalyzes a chemicalreaction resulting in the cleavage of a predetermined RNA moleculeassociated with a disease.

[0088] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of aprotein, for example a protein related to the maintenance or progressionof Alzheimer's disease, with the nucleic acid sensor molecule in asystem, the enzymatic nucleic acid component catalyzes a chemicalreaction resulting in the cleavage of a predetermined RNA moleculeassociated with a disease.

[0089] In one embodiment, the invention features a nucleic acid sensormolecule comprising an enzymatic nucleic acid component and one or moresensor components, wherein, in response to an interaction of a singlestranded RNA (ssRNA), for example a ssRNA related to the maintenance orprogression of Alzheimer's disease, with the nucleic acid sensormolecule in a system, the enzymatic nucleic acid component catalyzes achemical reaction resulting in ligation of a predetermined RNA moleculeto another predetermined RNA molecule.

[0090] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of asingle stranded DNA (ssDNA), for example a dsDNA related to themaintenance or progression of Alzheimer's disease, with the nucleic acidsensor molecule in a system, the enzymatic nucleic acid componentcatalyzes a chemical reaction resulting in ligation of a predeterminedRNA molecule to another predetermined RNA molecule.

[0091] In yet another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of apeptide, for example a peptide related to the maintenance or progressionof Alzheimer's disease, with the nucleic acid sensor molecule in asystem, the enzymatic nucleic acid component catalyzes a chemicalreaction resulting in ligation of a predetermined RNA molecule toanother predetermined RNA molecule.

[0092] In still another embodiment, the invention features a nucleicacid sensor molecule comprising an enzymatic nucleic acid component andone or more sensor components, wherein, in response to an interaction ofa protein, for example a protein related to the maintenance orprogression of Alzheimer's disease, with the nucleic acid sensormolecule in a system, the enzymatic nucleic acid component catalyzes achemical reaction resulting in ligation of a predetermined RNA moleculeto another predetermined RNA molecule.

[0093] In one embodiment, the invention features a method comprising:(a) contacting a nucleic acid sensor molecule of the invention with asystem comprising at least one ssRNA having a SNP related to themaintenance or progression of Alzheimer's disease, under conditionssuitable for the enzymatic nucleic acid component of the nucleic acidsensor molecule to catalyze a chemical reaction resulting in adetectable response; and (b) assaying for the detectable response.

[0094] In another embodiment, the invention features a methodcomprising: (a) contacting a nucleic acid sensor molecule of theinvention with a system comprising at least one ssDNA having a SNPrelated to the maintenance or progression of Alzheimer's disease, underconditions suitable for the enzymatic nucleic acid component of thenucleic acid sensor molecule to catalyze a chemical reaction resultingin a detectable response; and (b) assaying for the detectable response.

[0095] In another embodiment, the invention features a methodcomprising: (a) contacting a nucleic acid sensor molecule of theinvention with a system comprising at least one peptide related to themaintenance or progression of Alzheimer's disease, under conditionssuitable for the enzymatic nucleic acid component of the nucleic acidsensor molecule to catalyze a chemical reaction resulting in adetectable response; and (b) assaying for the detectable response.

[0096] In yet another embodiment, the invention features a methodcomprising: (a) contacting a nucleic acid sensor molecule of theinvention with a system comprising at least one protein related to themaintenance or progression of Alzheimer's disease, under conditionssuitable for the enzymatic nucleic acid component of the nucleic acidsensor molecule to catalyze a chemical reaction resulting in adetectable response; and (b) assaying for the detectable response.

[0097] In one embodiment, the invention features a method comprisingcontacting a nucleic acid sensor molecule of the invention with a systemcomprising at least one ssRNA related to the maintenance or progressionof Alzheimer's disease, under conditions suitable for the enzymaticnucleic acid component of the nucleic acid sensor molecule to cleave apredetermined RNA molecule.

[0098] In another embodiment, the invention features a method comprisingthe steps of contacting a nucleic acid sensor molecule of the inventionwith a system comprising at least one ssDNA related to the maintenanceor progression of Alzheimer's disease, under conditions suitable for theenzymatic nucleic acid component of the nucleic acid sensor molecule tocleave a predetermined RNA molecule In yet another embodiment, theinvention features a method comprising the steps of contacting a nucleicacid sensor molecule of the invention with a system comprising at leastone peptide related to the maintenance or progression of Alzheimer'sdisease, under conditions suitable for the enzymatic nucleic acidcomponent of the nucleic acid sensor molecule to cleave a predeterminedRNA molecule.

[0099] In another embodiment, the invention features a method comprisingthe steps of contacting a nucleic acid sensor molecule of the inventionwith a system comprising at least one protein related to the maintenanceor progression of Alzheimer's disease, under conditions suitable for theenzymatic nucleic acid component of the nucleic acid sensor molecule tocleave a predetermined RNA molecule.

[0100] In one embodiment, the invention features a method comprisingcontacting a nucleic acid sensor molecule of the invention with a systemcomprising at least one ssRNA having a SNP related to the maintenance orprogression of Alzheimer's disease, under conditions suitable for theenzymatic nucleic acid component of the nucleic acid sensor molecule toligate a predetermined RNA molecule to another predetermined RNAmolecule.

[0101] In another embodiment, the invention features a method comprisingthe steps of contacting a nucleic acid sensor molecule of the inventionwith a system comprising at least one ssDNA having a SNP related to themaintenance or progression of Alzheimer's disease, under conditionssuitable for the enzymatic nucleic acid component of the nucleic acidsensor molecule to ligate a predetermined RNA molecule to anotherpredetermined RNA molecule.

[0102] In yet another embodiment, the invention features a methodcomprising the steps of contacting a nucleic acid sensor molecule of theinvention with a system comprising at least one peptide related to themaintenance or progression of Alzheimer's disease, under conditionssuitable for the enzymatic nucleic acid component of the nucleic acidsensor molecule to ligate a predetermined RNA molecule to anotherpredetermined RNA molecule.

[0103] In another embodiment, the invention features a method comprisingthe steps of contacting a nucleic acid sensor molecule of the inventionwith a system comprising at least one protein related to the maintenanceor progression of Alzheimer's disease, under conditions suitable for theenzymatic nucleic acid component of the nucleic acid sensor molecule toligate a predetermined RNA molecule to another predetermined RNAmolecule.

[0104] In one embodiment, the invention features a method of using thenucleic acid sensor molecules of the invention to determine the functionor validate a predetermined gene target, a predetermined RNA target, apredetermined peptide target, or a predetermined protein target relatedto the maintenance or progression of Alzheimer's disease.

[0105] In another embodiment, the invention features a method of usingthe nucleic acid sensor molecules of the invention to determine agenotype or to characterize single nucleotide polymorphisms SNPs in agene or genome related to the maintenance or progression of Alzheimer'sdisease. In another embodiment, the invention features a method of usingthe nucleic acid sensor molecules of the invention to determine SNPscoring related to the maintenance or progression of Alzheimer'sdisease.

[0106] In another embodiment, the invention features a method of usingthe nucleic acid sensor molecules of the invention to determine aproteome, for example a disease specific proteome or treatment specificproteome related to the maintenance or progression of Alzheimer'sdisease. In yet another embodiment, the invention features a method ofusing the nucleic acid sensor molecules of the invention to determine aproteome map or to determine proteome scoring related to the maintenanceor progression of Alzheimer's disease.

[0107] In one embodiment, the invention features a method of using thenucleic acid sensor molecules of the invention to determine the dosageof a therapy used in treating a patient, to determine susceptibility ofa patient to disease, to determine drug metabolism in a patient, toselect a patient for a clinical trail, to determine a choice of therapyin a patient, or to treat a patient.

[0108] In another embodiment, the detection of a chemical reaction in amethod of the invention is indicative of the presence of the targetsignaling agent in the system.

[0109] In another embodiment, the absence of a chemical reaction in amethod of the invention is indicative of the system lacking the targetsignaling agent.

[0110] In one embodiment, a system of the invention is an in vitrosystem, for example a sample derived from a patient.

[0111] In another embodiment, a system of the invention is an in vivosystem, for example a mammal, mammalian cell, human, or human cell. Inanother embodiment, a component of a nucleic acid sensor molecule of theinvention comprises a hammerhead, hairpin, inozyme, G-cleaver, Zinzyme,RNase P EGS nucleic acid, DNAzyme or Amberzyme motif.

[0112] In one embodiment, a chemical reaction of a nucleic sensormolecule of the invention comprises cleavage of a phosphodiesterinternucleotide linkage, ligation of a predetermined nucleic acidmolecule to the nucleic acid sensor molecule, ligation of apredetermined nucleic acid molecule to another predetermined nucleicacid molecule, isomerization, phosphorylation of a peptide or protein,dephosphorylation of a peptide or protein, RNA polymerase activity, anincrease or decrease in fluorescence, an increase or decrease inenzymatic activity, an increase or decrease in the production of aprecipitate, an increase or decrease in chemoluminescence, or anincrease or decrease in radioactive emission.

[0113] In another embodiment, the invention features a kit comprising anucleic acid sensor molecule of the invention.

[0114] In another embodiment, the invention features an array of nucleicacid sensor molecules comprising a predetermined number of nucleic acidsensor molecules of the invention. In one embodiment, a nucleic acidsensor molecule of the instant invention is attached to a solid surface.Preferably, the surface of the instant invention comprises silicon-basedchips, silicon-based beads, controlled pore glass, polystyrene,cross-linked polystyrene, nitrocellulose, biotin, plastics, metals andpolyethylene films.

[0115] In one embodiment, the target signaling molecule of the inventioncomprises BACE, ps-2, and/or APP protein.

[0116] In another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of aBACE, ps-2, and/or APP peptide with the nucleic acid sensor molecule ina system, the enzymatic nucleic acid component catalyzes a chemicalreaction resulting in the cleavage of a predetermined RNA moleculeassociated with a disease, for example BACE, ps-2, and/or APP RNA.

[0117] In yet another embodiment, the invention features a nucleic acidsensor molecule comprising an enzymatic nucleic acid component and oneor more sensor components, wherein, in response to an interaction of aBACE, ps-2, and/or APP protein, with the nucleic acid sensor molecule ina system, the enzymatic nucleic acid component catalyzes a chemicalreaction resulting in the cleavage of a predetermined RNA moleculeassociated with a disease, for example BACE, ps-2, and/or APP RNA.

[0118] In another embodiment, the invention features a pharmaceuticalcomposition comprising a nucleic acid sensor molecule in apharmaceutically acceptable carrier.

[0119] In one embodiment, the invention features a method ofadministering to a cell, for example a mammalian cell or human cell, anucleic acid sensor molecule of the invention comprising contacting thecell with the nucleic acid sensor molecule under conditions suitable forthe administration. The method of administration can be in the presenceof a delivery reagent, for example a lipid, cationic lipid,phospholipid, or liposome.

[0120] In another embodiment, the invention features a cell, for examplea human cell, plant cell, bacterial cell, or fungal cell, including anucleic acid sensor molecule of the invention.

[0121] In another embodiment, the invention features an expressionvector comprising a nucleic acid sequence encoding at least one nucleicacid sensor molecule of the invention in a manner which allowsexpression of the nucleic acid sensor molecule.

[0122] In yet another embodiment, the invention features a mammaliancell, for example a human cell, including an expression vector of theinvention.

[0123] In one embodiment, an expression vector of the invention furthercomprises a sequence for a nucleic acid sensor molecule complementary toan RNA having BACE, ps-2, and/or APP sequence.

[0124] In another embodiment, an expression vector of the inventioncomprises a nucleic acid sequence encoding two or more nucleic acidsensor molecules, which can be the same or different.

[0125] In another embodiment, a predetermined RNA of the invention isassociated with Alzheimer's disease.

[0126] In another embodiment, the method of the instant invention iscarried out more than once.

[0127] By “inhibit”, “down-regulate”, or “reduce”, it is meant that theexpression of the gene, or level of RNAs or equivalent RNAs encoding oneor more protein subunits, or activity of one or more protein subunits,such as BACE, ps-2, or APP, is reduced below that observed in theabsence of the nucleic acid molecules of the invention. In oneembodiment, inhibition, down-regulation or reduction with a nucleic acidmolecule preferably is below that level observed in the presence of anenzymatically inactive or attenuated molecule that is able to bind tothe same site on the target RNA, but is unable to cleave that RNA. Inanother embodiment, inhibition, down-regulation, or reduction withantisense oligonucleotides is preferably below that level observed inthe presence of, for example, an oligonucleotide with scrambled sequenceor with mismatches. In another embodiment, inhibition, down-regulation,or reduction of BACE, ps-2, or APP with the nucleic acid molecule of theinstant invention is greater in the presence of the nucleic acidmolecule than in its absence.

[0128] By “modulate” is meant that the expression of the gene, or levelof RNAs or equivalent RNAs encoding one or more protein subunits, oractivity of one or more protein subunit(s) is up-regulated ordown-regulated, such that the expression, level, or activity is greaterthan or less than that observed in the absence of the nucleic acidmolecules of the invention.

[0129] By “up-regulate” is meant that the expression of the gene, orlevel of RNAs or equivalent RNAs encoding one or more protein subunits,or activity of one or more protein subunits, such as BACE, PS-2, or APPsubunit(s), is greater than that observed in the absence of the nucleicacid molecules of the invention. For example, the expression of a gene,such as BACE, PS-2, or APP gene, can be increased in order to treat,prevent, ameliorate, or modulate a pathological condition caused orexacerbated by an absence or low level of gene expression.

[0130] By “enzymatic nucleic acid molecule” it is meant a nucleic acidmolecule that has complementarity in a substrate binding region to aspecified gene target, and also has an enzymatic activity which isactive to specifically cleave target RNA. That is, the enzymatic nucleicacid molecule is able to intermolecularly cleave RNA and therebyinactivate a target RNA molecule. These complementary regions allowsufficient hybridization of the enzymatic nucleic acid molecule to thetarget RNA and thus permit cleavage. One hundred percent complementarityis preferred, but complementarity as low as 50-75% may also be useful inthis invention. The nucleic acids may be modified at the base, sugar,and/or phosphate groups. The term enzymatic nucleic acid is usedinterchangeably with phrases such as ribozymes, catalytic RNA, enzymaticRNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatableribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme,endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNAenzyme. All of these terminologies describe nucleic acid molecules withenzymatic activity. The specific enzymatic nucleic acid moleculesdescribed in the instant application are not meant to be limiting andthose skilled in the art will recognize that all that is important in anenzymatic nucleic acid molecule of this invention is that it have aspecific substrate binding site which is complementary to one or more ofthe target nucleic acid regions, and that it have nucleotide sequenceswithin or surrounding that substrate binding site which impart a nucleicacid cleaving activity to the molecule (Cech et al., U.S. Pat. No.4,987,071; Cech et al., 1988, JAMA).

[0131] The term “nucleic acid sensor molecule” “aptazyme” or “allozyme”as used herein refers to an allosteric enzymatic nucleic acid moleculesuch as the nucleic acid sensor molecules described herein or otherallosteric nucleic acid molecules, for example as described by George etal., U.S. Pat. No. 5,834,186 and U.S. Pat. No. 5,741,679, Shih et al.,U.S. Pat. No. 5,589,332, Nathan et al., U.S. Pat. No 5,871,914, Nathanand Ellington, International PCT publication No. WO 00/24931, Breaker etal., International PCT Publication Nos. WO 00/26226 and 98/27104,Sullenger et al., International PCT publication No. WO 99/29842, Usmanet al., U.S. Ser. No. 09/800,594 and U.S. Ser. No. 09/877,526.

[0132] By “halfzyme” is meant an enzymatic nucleic acid moleculeassembled from two or more nucleic acid components. The enzymaticnucleic acid in the halfzyme configuration is active when all thenecessary components interact with each other. The halfzyme constructcan be engineered to have a component lacking from the structure orsequence of the enzymatic nucleic acid molecule such that enzymaticactivity is inhibited. In the presence of the target signaling agent,the required component for enzymatic activity is provided such that thehalfzyme is catalytically active (see for example FIG. 6).By “enzymaticportion” or “catalytic domain” is meant that portion/region of theenzymatic nucleic acid molecule essential for cleavage of a nucleic acidsubstrate (for example see FIGS. 1-5).

[0133] By “substrate binding arm” or “substrate binding domain” is meantthat portion/region of a ribozyme which is complementary to (i.e., ableto base-pair with) a portion of its substrate. Generally, suchcomplementarity is 100%, but can be less if desired. For example, as fewas 10 bases out of 14 may be base-paired. Such arms are shown generallyin FIGS. 1-5. That is, these arms contain sequences within a ribozymewhich are intended to bring ribozyme and target RNA together throughcomplementary base-pairing interactions. The ribozyme of the inventionmay have binding arms that are contiguous or non-contiguous and may beof varying lengths. The length of the binding arm(s) are preferablygreater than or equal to four nucleotides and of sufficient length tostably interact with the target RNA; a specific embodiment 12-100nucleotides; more preferably 14-24 nucleotides long. If two binding armsare chosen, the design is such that the length of the binding arms aresymmetrical (i.e., each of the binding arms is of the same length; e.g.,five and five nucleotides, six and six nucleotides or seven and sevennucleotides long) or asymmetrical (i.e., the binding arms are ofdifferent length; e.g., six and three nucleotides; three and sixnucleotides long; four and five nucleotides long; four and sixnucleotides long; four and seven nucleotides long; and the like).

[0134] The term “Inozyme” or “NCH” motif as used herein, refers to anenzymatic nucleic acid molecule comprising a motif as is generallydescribed as NCH Rz in FIG. 2. Inozymes possess endonuclease activity tocleave RNA substrates having a cleavage triplet NCH/, where N is anucleotide, C is cytidine and H is adenosine, uridine or cytidine, and /represents the cleavage site. H is used interchangeably with X. Inozymescan also possess endonuclease activity to cleave RNA substrates having acleavage triplet NCN/, where N is a nucleotide, C is cytidine, and /represents the cleavage site. “I” in FIG. 2 represents an Inosinenucleotide, preferably a ribo-Inosine or xylo-Inosine nucleoside. Seefor example, Ludwig et al., U.S. Serial No. 60/156,236, filed Sep. 27,1999, entitled “COMPOSITIONS HAVING RNA CLEAVING ACTIVITY”, and Ludwiget al., International PCT Publication No. WO 98/58058.

[0135] The term “G-cleaver” motif as used herein, refers to an enzymaticnucleic acid molecule comprising a motif as is generally described asG-cleaver Rz in FIG. 2. G-cleavers possess endonuclease activity tocleave RNA substrates having a cleavage triplet NYN/, where N is anucleotide, Y is uridine or cytidine and / represents the cleavage site.G-cleavers can be chemically modified as is generally shown in FIG. 2.See for example Eckstein et al., U.S. Ser. No. 09/444,209, entitled“NUCLEIC ACID CATALYSTS WITH ENDONUCLEASE ACTIVITY,” which was filed onNov. 19, 1999 and which is a continuation-in-part of U.S. Ser. No.09/159,274, and Eckstein et al., International PCT Publication No. WO99/16871.

[0136] The term “amberzyme” motif as used herein, refers to an enzymaticnucleic acid molecule comprising a motif as is generally described inFIG. 3. Amberzymes possess endonuclease activity to cleave RNAsubstrates having a cleavage triplet NG/N, where N is a nucleotide, G isguanosine, and / represents the cleavage site. Amberzymes can bechemically modified to increase nuclease stability through substitutionsas are generally shown in FIG. 3. In addition, differing nucleosideand/or non-nucleoside linkers can be used to substitute the 5′-gaaa-3′loops shown in the figure. Amberzymes represent a non-limiting exampleof an enzymatic nucleic acid molecule that does not require aribonucleotide (2′-OH) group within its own nucleic acid sequence foractivity. See for example Beigelman et al., U.S. Ser. No. 09/301,511filed Apr. 28, 1999, entitled “NUCLEOTIDE TRIPHOSPHATES AND THEIRINCORPORATION INTO OLIGONUCLEOTIDES” and Beigelman et al., InternationalPCT Publication No. WO 99/55857.

[0137] The term “zinzyme” motif as used herein, refers to an enzymaticnucleic acid molecule comprising a motif as is generally described inFIG. 4. Zinzymes possess endonuclease activity to cleave RNA substrateshaving a cleavage triplet including but not limited to YG/Y, where Y isuridine or cytidine, and G is guanosine and / represents the cleavagesite. Zinzymes can be chemically modified to increase nuclease stabilitythrough substitutions as are generally shown in FIG. 4, includingsubstituting 2′-O-methyl guanosine nucleotides for guanosinenucleotides. In addition, differing nucleotide and/or non-nucleotidelinkers can be used to substitute the 5′-gaaa-2′ loop shown in thefigure. Zinzymes represent a non-limiting example of an enzymaticnucleic acid molecule that does not require a ribonucleotide (2′-OH)group within its own nucleic acid sequence for activity. See for exampleBeigelman et al., U.S. Ser. No. 09/301,511 filed Apr. 28, 1999, entitled“NUCLEOTIDE TRIPHOSPHATES AND THEIR INCORPORATION INTO OLIGONUCLEOTIDES”and Beigelman et a., International PCT Publication No. WO 99/55857.

[0138] The term ‘DNAzyme’ as used herein, refers to an enzymatic nucleicacid molecule that does not require the presence of a 2′-OH group forits activity. In particular embodiments the enzymatic nucleic acidmolecule can have an attached linker(s) or other attached or associatedgroups, moieties, or chains containing one or more nucleotides with2′-OH groups. DNAzymes can be synthesized chemically or expressedendogenously in vivo, by means of a single stranded DNA vector orequivalent thereof. An example of a DNAzyme is shown in FIG. 5 and isgenerally reviewed in Usman et al., International PCT Publication No. WO95/11304; Chartrand et al., 1995, NAR 23, 4092; Breaker et al., 1995,Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262; Breaker, 1999,Nature Biotechnology, 17, 422423; and Santoro et. al., 2000, J. Am.Chem. Soc., 122, 2433-39. Additional DNAzyme motifs can be selected forusing techniques similar to those described in these references, andhence, are within the scope of the present invention.

[0139] By “decoy” is meant a nucleic acid molecule or aptamer that isdesigned to preferentially bind to a predetermined ligand. Such bindingcan result in the inhibition or activation of a target molecule. Thedecoy RNA or aptamer can compete with a naturally occurring bindingtarget for the binding of a specific ligand. For example, it has beenshown that over-expression of HIV trans-activation response (TAR) RNAcan act as a “decoy” and efficiently binds HIV tat protein, therebypreventing it from binding to TAR sequences encoded in the HIV RNA(Sullenger et al., 1990, Cell, 63, 601-608). This is but a specificexample and those in the art will recognize that other embodiments canbe readily generated using techniques generally known in the art, seefor example Gold et al., 1995, Annu. Rev. Biochem., 64, 763; Brody andGold, 2000, J. Biotechnol., 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2,100; Kusser, 2000, J Biotechnol., 74, 27; Hermann and Patel, 2000,Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628.Similarly, a decoy RNA can be designed to bind to a EGFR receptor andblock the binding of EGFR or a decoy RNA can be designed to bind to EGFRand prevent interaction with the EGFR receptor.

[0140] By “RNA interference” as used herein refers to the degradation oftarget RNA molecules mediated by double stranded RNA molecules in whichone strand of the double stranded RNA is complementary to the targetRNA. RNA interference is mediated by short interfering RNA “siRNA”, seefor example Bass, 2001, Nature, 411, 428429; Elbashir et al., 2001,Nature, 411, 494-498).

[0141] The term “double stranded RNA” or “dsRNA” as used herein refersto a double stranded RNA molecule capable of RNA interference, includingshort interfering RNA “siRNA” see for example Bass, 2001, Nature, 411,428-429; Elbashir et al., 2001, Nature, 411, 494-498).

[0142] By “sufficient length” is meant an oligonucleotide of greaterthan or equal to 3 nucleotides. In connection with the binding arms ofan enzymatic nucleic acid molecule, “sufficient length” means that thebinding arms are long enough to provide a stable interaction with atarget RNA under the expected conditions. Preferably the binding armsare not so long as to prevent a useful level of turnover.

[0143] By “stably interact” is meant, interaction of theoligonucleotides with target nucleic acid (e.g., by forming hydrogenbonds with complementary nucleotides in the target under physiologicalconditions).

[0144] By “equivalent” RNA to BACE is meant to include those naturallyoccurring RNA molecules having homology (partial or complete) to RNAencoding BACE proteins or encoding for proteins with similar function asBACE in various organisms, including human, rodent, primate, rabbit,pig, protozoans, fungi, plants, and other microorganisms and parasites.The equivalent RNA sequence also includes in addition to the codingregion, regions such as 5′-untranslated region, 3′-untranslated region,introns, intron-exon junction and the like.

[0145] By “equivalent” RNA to ps-2 is meant to include those naturallyoccurring RNA molecules having homology (partial or complete) to RNAencoding ps-2 proteins or encoding for proteins with similar function asps-2 in various organisms, including human, rodent, primate, rabbit,pig, protozoans, fungi, plants, and other microorganisms and parasites.The equivalent RNA sequence also includes in addition to the codingregion, regions such as 5′-untranslated region, 3′-untranslated region,introns, intron-exon junction and the like.

[0146] By “equivalent” RNA to APP is meant to include those naturallyoccurring RNA molecules having homology (partial or complete) to RNAencoding APP proteins or encoding for proteins with similar function asAPP in various organisms, including human, rodent, primate, rabbit, pig,protozoans, fungi, plants, and other microorganisms and parasites. Theequivalent RNA sequence also includes in addition to the coding region,regions such as 5′-untranslated region, 3′-untranslated region, introns,intron-exon junction and the like.

[0147] By “homology” is meant the nucleotide sequence of two or morenucleic acid molecules is partially or completely identical. Preferably,the sequences are at least 70%, 80%, 90%, or 95% identical over ananalysis window of at least 50 or 100 contiguous nucleotides.

[0148] By “antisense nucleic acid” it is meant a non-enzymatic nucleicacid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA orRNA-PNA (protein nucleic acid; Egholm et al., 1993 Nature 365, 566)interactions and alters the activity of the target RNA (for a review seeStein and Cheng, 1993 Science 261, 1004). Typically, antisense moleculeswill be complementary to a target sequence along a single contiguoussequence of the antisense molecule. However, in certain embodiments, anantisense molecule may bind to substrate such that the substratemolecule forms a loop, and/or an antisense molecule may bind such thatthe antisense molecule forms a loop. Thus, the antisense molecule may becomplementary to two (or even more) non-contiguous substrate sequencesor two (or even more) non-contiguous sequence portions of an antisensemolecule may be complementary to a target sequence or both.

[0149] By “2-5A antisense chimera” it is meant, an antisenseoligonucleotide containing a 5′ phosphorylated 2′-5′-linked adenylateresidues. These chimeras bind to target RNA in a sequence-specificmanner and activate a cellular 2-5A-dependent ribonuclease which, inturn, cleaves the target RNA (Torrence et al., 1993 Proc. Natl. Acad.Sci. USA 90, 1300).

[0150] By “triplex DNA” it is meant an oligonucleotide that can bind toa double-stranded DNA in a sequence-specific manner to form atriple-strand helix. Formation of such triple helix structure has beenshown to inhibit transcription of the targeted gene (Duval-Valentin etal., 1992 Proc. Natl. Acad. Sci. USA 89, 504).

[0151] By “gene” it is meant a nucleic acid that encodes an RNA.

[0152] By “amyloid precursor protein” or “APP” is meant, a protein,protein fragment, or peptide comprising the type I transmembraneprotein, β-amyloid precursor protein (see for example Kang et al., 1987,Nature, 325, 733). The terms amyloid precursor protein and APP alsorefer to mutant proteins, protein fragments, or peptides comprising thetype I transmembrane protein, β-amyloid precursor protein, such asproteins encoded by Swedish mutant APP, where a Lys to Asn or Met to Leusubstitution at the P1 position of APP is thought to result in earlyonset Alzheimer's disease (see for example Mullan et al., 1992, Nat.Genet., 1, 345-7).

[0153] By “signaling agent” or “target signaling agent” is meant achemical or physical entity capable of interacting with a nucleic acidsensor molecule, specifically a sensor component of a nucleic acidsensor molecule, resulting in modification of the enzymatic nucleic acidcomponent of the nucleic acid sensor molecule via chemical, physical,topological, or conformational changes to the structure of the moleculesuch that the activity of the enzymatic nucleic acid component ismodulated, for example is activated or deactivated. Signaling agents cancomprise target signaling molecules such as macromolecules, ligands,small molecules, metals and ions, nucleic acid molecules including butnot limited to RNA and DNA or analogs thereof, proteins, peptides,antibodies, polysaccharides, lipids, sugars, microbial or cellularmetabolites, pharmaceuticals, and organic and inorganic molecules in apurified or unpurified form, or physical signals including magnetism,temperature, light, sound, shock, pH, capacitance, voltage, and ionicconditions. Exemplary signaling agents of the instant invention includemolecules associated with the progression and/or maintenance ofAlzheimer's disease.

[0154] By “system” is meant, material, in a purified or unpurified form,from biological or non-biological sources, including but not limited tohuman, animal, plant, bacteria, virus, fungi, soil, water, mechanicaldevices, circuits, networks, computers, or others that comprises thetarget signaling agent or target signaling molecule to be detected oramplified. System also refers to a group of substances or componentsthat can be collectively combined or identified. A system can comprise abiological system, for example an organism, cell, or components,extracts, and samples thereof. A system can further comprise anexperimental or artificial system, where various substances orcomponents are intentionally combined together.

[0155] The “biological system” as used herein can be a eukaryotic systemor a prokaryotic system, for example a bacterial cell, plant cell or amammalian cell, or of plant origin, mammalian origin, yeast origin,Drosophila origin, or archebacterial origin.

[0156] By “reporter molecule” is meant a molecule, such as a nucleicacid sequence (e.g., RNA or DNA or analogs thereof) or peptides and/orother chemical moieties, able to stably interact with the nucleic acidsensor molecule and function as a substrate for the nucleic acid sensormolecule.

[0157] The reporter molecule can also contain chemical moieties capableof generating a detectable response, including but not limited to,fluorescent, chromogenic, radioactive, enzymatic and/or chemiluminescentor other detectable labels that can then be detected using standardassays known in the art. The reporter molecule can also act as anintermediate in a chain of events, for example, by acting as anamplicon, inducer, promoter, or inhibitor of other events that can actas second messengers in a system.

[0158] In one embodiment, the reporter molecule of the invention is anoligonucleotide primer, template, or probe, which can be used tomodulate the amplification of additional nucleic acid sequences, forexample, sequences comprising reporter molecules, target signalingmolecules, effector molecules, inhibitor molecules, and/or additionalnucleic acid sensor molecules of the instant invention.

[0159] By “sensor component” of the nucleic acid sensor molecule ismeant, a molecule such as a nucleic acid sequence (e.g., RNA or DNA oranalogs thereof), peptide, or other chemical moiety which can interactwith one or more regions of the enzymatic nucleic acid component of thenucleic acid sensor molecule to modulate, such as inhibit or activate,the catalytic activity of the nucleic acid sensor molecule. In thepresence of a signaling agent, the ability of the sensor component, forexample, to modulate the catalytic activity of the enzymatic nucleicacid component is inhibited or diminished. The sensor component cancomprise recognition properties relating to chemical or physical signalscapable of modulating the enzymatic nucleic acid component via chemicalor physical changes to the structure of the nucleic acid sensormolecule. The sensor component can be derived from a naturally occurringnucleic acid protein binding sequence, for example RNAs that bind toproteins and/or nucleic acid molecules associated with nuerodegenerativediseases such as Alzheimer's disease, for example APP, BACE, or ps-2peptides, proteins, DNA, or RNA. The sensor component can also bederived from a nucleic acid sequence that is obtained through in vitroor in vivo selection techniques as are know in the art. Such sequencesor “aptamers” can be designed to bind a specific protein, peptide,nucleic acid, co-factor, metabolite, drug, or other small molecule withvarying affinity. The sensor component can be covalently linked to thenucleic acid sensor molecule, or can be non-covalently associated. Aperson skilled in the art will recognize that all that is required isthat the sensor component is able to selectively inhibit the activity ofthe nucleic acid sensor molecule.

[0160] In a preferred embodiment the linker region, when present in thenucleic acid sensor molecule and/or reporter molecule is furthercomprised of nucleotide, non-nucleotide chemical moieties orcombinations thereof. Non-limiting examples of non-nucleotide chemicalmoieties can include ester, anhydride, amide, nitrile, and/or phosphategroups.

[0161] By “nucleic acid circuit” or “nucleic acid-based circuit” ismeant an electronic circuit comprising one or more nucleic acids oroligonucleotides.

[0162] By “nucleic acid computer” or “nucleic acid-based computer” ismeant a computing device or system comprising one or more nucleic acidsor oligonucleotides. The nucleic acid computer can be used to interfacebiological systems, control other devices, or can be utilized to solveproblems and/or manipulate data. Furthermore, the nucleic acid computercan comprise nucleic acid circuits.

[0163] By “predetermined RNA molecule” is meant a particular RNAmolecule of known sequence, such as a cellular RNA, viral RNA, messengerRNA, transfer RNA, ribosomal RNA etc.

[0164] By “detectable response” is meant a chemical or physical propertythat can be measured, including, but not limited to changes intemperature, pH, frequency, charge, capacitance, or changes influorescent, chromogenic, radioactive, enzymatic and/or chemiluminescentlevels or properties that can then be detected using standard methodsknown in the art.

[0165] By “single stranded RNA” (ssRNA) is meant a naturally occurringor synthetic ribonucleic acid molecule comprising a linear singlestrand, for example a ssRNA can be a messenger RNA (mRNA), transfer RNA(tRNA), ribosomal RNA (rRNA) etc. of a gene associated with aneurodegenerative disease, such as BACE, APP, or ps-2.

[0166] By “single stranded DNA” (ssDNA) is meant a naturally occurringor synthetic deoxyribonucleic acid molecule comprising a linear singlestrand, for example, a ssDNA can be a sense or antisense gene sequence,single nucleotide polymorphism (SNP), or EST (Expressed Sequence Tag)associated with a neurodegenerative disease, such as Alzheimer'sdisease, such as an EST or SNP associated with familial early onsetAlzheimer's disease.

[0167] By “predetermined target” is meant a signaling agent or targetsignaling agent that is chosen to interact with a nucleic acid sensormolecule to generate a detectable response, for example a protein,peptide, RNA or DNA associated with a neurodegenerative disease such asAlzheimer's disease.

[0168] By “validate a predetermined gene target” is meant to confirmthat a particular gene is associated with a specific phenotype, disease,or biological function in a system. Once the relationship between a geneand its function or resulting phenotype is determined, the gene can betargeted to modulate the activity of the gene.

[0169] By “validate a predetermined RNA target” is meant to confirm thata particular RNA transcript of a gene or other RNA is associated with aspecific phenotype, disease, or biological function in a system, forexample Alzheimer's disease or the presence of beta-amyloid protein.Once the relationship between the RNA and its function or resultingphenotype is determined, the RNA can be targeted to modulate theactivity of the RNA or the gene encoding the RNA.

[0170] By “validate a predetermined peptide target” is meant to confirmthat a particular peptide is associated with a specific phenotype,disease, or biological function in a system, for example Alzheimer'sdisease or the presence of beta-amyloid protein. Once the relationshipbetween the peptide and its function or resulting phenotype isdetermined, the peptide or RNA encoding the peptide can be targeted tomodulate the activity of the peptide or the gene encoding the peptide.

[0171] By “validate a predetermined protein target” is meant to confirmthat a particular protein is associated with a specific phenotype,disease, or biological function in a system, for example Alzheimer'sdisease or the presence of beta-amyloid protein. Once the relationshipbetween the protein and its function or resulting phenotype isdetermined, the protein or RNA encoding the protein can be targeted tomodulate the activity of the protein or the gene encoding the protein.

[0172] By “validate a predetermined SNP target” is meant to confirm thata particular SNP of a gene is associated with a specific phenotype,disease, or biological function in a system, for example Alzheimer'sdisease or the presence of beta-amyloid protein. Once the relationshipbetween the SNP and its function, associated gene function, or resultingphenotype is determined, the SNP can be targeted to modulate theactivity of the SNP or the gene associated with the SNP.

[0173] By “SNP scoring” is meant a process of identifying and measuringthe presence of SNPs in a genome, for example SNPs associated withneurodegenerative disease, such as Alzheimer's disease. SNP scoring canalso refer to a system of ranking single nucleotide polymorphisms interms of the relationship between a particular SNP and a certain diseasestate such as Alzheimer's disease or drug response in an organism, forexample a human. SNP scoring can be used in determining the genotype ofan organism.

[0174] By “SNP” is meant a single nucleotide polymorphism as is known inthe art to include single nucleotide substitutions or mismatches in agenome (see Brookes, 1999, Gene, 234, 177-186; Stephens, 1999, MolecularDiagnosis, 4, 309-317). SNPs can be used to identify genes and genefunctions as well as to characterize a genotype.

[0175] By “proteome” is meant the complete set of proteins found in aparticular system, such as a cell or organism, for example a human cellor human.

[0176] By “proteome map” is meant the functional relationship betweendifferent protein constituents of a proteome.

[0177] By “proteome scoring” is meant a process of identifying andmeasuring the presence of proteins in a proteome. Proteome scoring canalso refer to a system of ranking protiens in terms of the relationshipbetween a particular protein and a certain disease state or drugresponse in an organism, for example a human. Proteome scoring can beused in determining the phenotype of an organism.

[0178] By “disease specific proteome” is meant a proteome associatedwith a particular disease or condition.

[0179] By “treatment specific proteome” is meant a proteome associatedwith a particular treatment or therapy.

[0180] By “complementarity” is meant that a nucleic acid can formhydrogen bond(s) with another RNA sequence by either traditionalWatson-Crick or other non-traditional types. In reference to the nucleicmolecules of the present invention, the binding free energy for anucleic acid molecule with its target or complementary sequence issufficient to allow the relevant function of the nucleic acid toproceed, e.g., ribozyme cleavage, antisense or triple helix inhibition.Determination of binding free energies for nucleic acid molecules iswell known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant.Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783-3785.) Apercent complementarity indicates the percentage of contiguous residuesin a nucleic acid molecule which can form hydrogen bonds (e.g.,Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5,6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100%complementary). “Perfectly complementary” means that all the contiguousresidues of a nucleic acid sequence will hydrogen bond with the samenumber of contiguous residues in a second nucleic acid sequence.

[0181] At least seven basic varieties of naturally-occurring enzymaticRNAs are known presently. Each can catalyze the hydrolysis of RNAphosphodiester bonds in trans (and thus can cleave other RNA molecules)under physiological conditions. Table I summarizes some of thecharacteristics of these ribozymes. In general, enzymatic nucleic acidsact by first binding to a target RNA. Such binding occurs through thetarget binding portion of a enzymatic nucleic acid which is held inclose proximity to an enzymatic portion of the molecule that acts tocleave the target RNA. Thus, the enzymatic nucleic acid first recognizesand then binds a target RNA through complementary base-pairing, and oncebound to the correct site, acts enzymatically to cut the target RNA.Strategic cleavage of such a target RNA will destroy its ability todirect synthesis of an encoded protein. After an enzymatic nucleic acidhas bound and cleaved its RNA target, it is released from that RNA tosearch for another target and can repeatedly bind and cleave newtargets. Thus, a single ribozyme molecule is able to cleave manymolecules of target RNA. In addition, the ribozyme is a highly specificinhibitor of gene expression, with the specificity of inhibitiondepending not only on the base-pairing mechanism of binding to thetarget RNA, but also on the mechanism of target RNA cleavage. Singlemismatches, or base-substitutions, near the site of cleavage cancompletely eliminate catalytic activity of a ribozyme.

[0182] The enzymatic nucleic acid molecules that cleave the specifiedsites in BACE-specific RNAs and/or ps-2-specific RNAs represent a noveltherapeutic approach to treat a variety of pathologic indications,including Alzheimer's disease and dementia.

[0183] In one of the embodiments of the inventions described herein, theenzymatic nucleic acid molecule is formed in a hammerhead or hairpinmotif, but may also be formed in the motif of a hepatitis delta virus,group I intron, group II intron or RNase P RNA (in association with anRNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs,or G-cleavers. Examples of such hammerhead motifs are described byDreyfus, supra, Rossi et al., 1992, AIDS Research and Human Retroviruses8, 183. Examples of hairpin motifs by Hampel et al., EP0360257; Hampeland Tritz, 1989 Biochemistry 28, 4929; Feldstein et al., 1989, Gene 82,53; Haseloff and Gerlach, 1989, Gene, 82, 43; Hampel et al., 1990Nucleic Acids Res. 18, 299; Chowrira & McSwiggen, U.S. Pat. No.5,631,359. Examples of the hepatitis delta virus motif is described byPerrotta and Been, 1992 Biochemistry 31, 16. The RNase P motif isdescribed by Guerrier-Takada et al., 1983 Cell 35, 849; Forster andAltman, 1990, Science 249, 783; Li and Altman, 1996, Nucleic Acids Res.24, 835. Neurospora VS RNA ribozyme motif is described by Collins(Saville and Collins, 1990 Cell 61, 685-696; Saville and Collins, 1991Proc. Natl. Acad. Sci. USA 88, 8826-8830; Collins and Olive, 1993Biochemistry 32, 2795-2799; Guo and Collins, 1995, EMBO. J. 14, 363).Group II introns are described by Griffin et al., 1995, Chem. Biol. 2,761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al.,International PCT Publication No. WO 96/22689. The Group I intron motifis described by Cech et al., U.S. Pat. No. 4,987,071 and of DNAzymes byUsman et al., International PCT Publication No. WO 95/11304; Chartrandet al., 1995, NAR 23, 4092; Breaker et al., 1995, Chem. Bio. 2, 655;Santoro et al., 1997, PNAS 94, 4262. NCH cleaving motifs are describedin Ludwig & Sproat, International PCT Publication No. WO 98/58058; andG-cleavers are described in Kore et al., 1998, Nucleic Acids Research26, 4116-4120 and Eckstein et al., International PCT Publication No. WO99/16871. Additional motifs such as the Aptazyme (Breaker et al., WO98/43993), Amberzyme (FIG. 3; Beigelman et al., U.S. Ser. No.09/301,511) and Zinzyme (Beigelman et al., U.S. Ser. No. 09/301,511).All these references are incorporated by reference herein, includingdrawings. Any of these motifs can be used in the present invention.These specific motifs are not limiting in the invention and thoseskilled in the art will recognize that all that is important in anenzymatic nucleic acid molecule of this invention is that it has aspecific substrate binding site which is complementary to one or more ofthe target gene RNA regions, and that it have nucleotide sequenceswithin or surrounding that substrate binding site which impart an RNAcleaving activity to the molecule (Cech et al., U.S. Pat. No.4,987,071).

[0184] In certain embodiments of the present invention, a nucleic acidmolecule, e.g., an enzymatic nucleic acid molecule, allozyme, antisensemolecule, or triplex DNA, is 13 to 100 nucleotides in length, e.g., inspecific embodiments 35, 36, 37, or 38 nucleotides in length (e.g., forparticular ribozymes or antisense). In particular embodiments, thenucleic acid molecule is 15-100, 17-100, 20-100, 21-100, 23-100, 25-100,27-100, 30-100, 32-100, 35-100, 40-100, 50-100, 60-100, 70-100, or80-100 nucleotides in length. Instead of 100 nucleotides being the upperlimit on the length ranges specified above, the upper limit of thelength range can be, for example, 30, 40, 50, 60, 70, or 80 nucleotides.Thus, for any of the length ranges, the length range for particularembodiments has lower limit as specified, with an upper limit asspecified which is greater than the lower limit. For example, in aparticular embodiment, the length range can be 35-50 nucleotides inlength. All such ranges are expressly included. Also in particularembodiments, a nucleic acid molecule can have a length which is any ofthe lengths specified above, for example, 21 nucleotides in length.

[0185] In one embodiment, the invention provides a method for producinga class of nucleic acid-based gene-inhibiting agents which exhibit ahigh degree of specificity for the RNA of a desired target. For example,the enzymatic nucleic acid molecule is preferably targeted to a highlyconserved sequence region of target RNAs encoding BACE proteins(specifically BACE gene) such that specific treatment of a disease orcondition can be provided with either one or several nucleic acidmolecules of the invention. Such nucleic acid molecules can be deliveredexogenously to specific tissue or cellular targets as required.Alternatively, the nucleic acid molecules (e.g., ribozymes andantisense) can be expressed from DNA and/or RNA vectors that aredelivered to specific cells.

[0186] By “BACE proteins” is meant, a protein or a mutant proteinderivative thereof, comprising secretase associated proteolytic cleavageactivity of APP. In particular embodiments, the BACE protein can bereferred to by other names used to describe a β-secretase, such as Asp2(Gurney, 1999, Nature, 402, 533-537).

[0187] By “highly conserved sequence region” is meant, a nucleotidesequence of one or more regions in a target gene does not varysignificantly from one generation to the other or from one biologicalsystem to the other as understood by those skilled in the art.

[0188] The nucleic acid-based inhibitors of BACE, ps-2, or APPexpression are useful for the prevention of the diseases and conditionsAlzheimer's disease, dementia, and any other diseases or conditions thatare related to the levels of BACE, ps-2, or APP in a cell or tissue.Thus, the reduction of BACE, ps-2, or APP expression (specifically BACE,ps-2, or APP gene RNA levels} and thus reduction in the level of therespective protein relieves, to some extent, the symptoms of the diseaseor condition.

[0189] The nucleic acid-based inhibitors of the invention can be addeddirectly, or can be complexed with cationic lipids, packaged withinliposomes, or otherwise delivered to target cells or tissues. Thenucleic acid or nucleic acid complexes can be locally administered torelevant tissues ex vivo, or in vivo through injection, infusion pump orstent, with or without their incorporation in biopolymers. In preferredembodiments, the enzymatic nucleic acid inhibitors comprise sequences,which are complementary to the substrate sequences in Tables III toVIII. Examples of such enzymatic nucleic acid molecules also are shownin Tables III to VIII. Examples of such enzymatic nucleic acid moleculesconsist essentially of sequences defined in these Tables.

[0190] In yet another embodiment, the invention features antisensenucleic acid molecules and 2-5A chimera including sequencescomplementary to the substrate sequences shown in Tables III to VIII.Such nucleic acid molecules can include sequences as shown for thebinding arms of the enzymatic nucleic acid molecules in Tables III toVIII. Similarly, triplex molecules can be provided targeted to thecorresponding DNA target regions, and containing the DNA equivalent of atarget sequence or a sequence complementary to the specified target(substrate) sequence. Typically, antisense molecules will becomplementary to a target sequence along a single contiguous sequence ofthe antisense molecule. However, in certain embodiments, an antisensemolecule may bind to substrate such that the substrate molecule forms aloop, and/or an antisense molecule may bind such that the antisensemolecule forms a loop. Thus, the antisense molecule may be complementaryto two (or even more) non-contiguous substrate sequences or two (or evenmore) non-contiguous sequence portions of an antisense molecule may becomplementary to a target sequence or both.

[0191] By “consists essentially of” is meant that the active enzymaticnucleic acid molecule of the invention contains an enzymatic center orcore equivalent to those in the examples, and binding arms able to bindRNA such that cleavage at the target site occurs. Other sequences may bepresent which do not interfere with such cleavage. Thus, a core regionmay, for example, include one or more loop or stem-loop structures,which do not prevent enzymatic activity. Such sequences can bedesignated as “X”, for example, as in a loop or stem/loop structure. Forexample, a core sequence for a hammerhead enzymatic nucleic acid can be5′-CUGAUGAG-3′ and 5′-CGAA-3′ connected by “X”, where X=5′-GCCGUUAGGC-3′(SEQ ID NO: 4550), or any other stem II region known in the art.Similarly, for other enzymatic nucleic acid molecules of the instantinvention, additional sequences may be present that do not interferewith the function of the nucleic acid molecule.

[0192] In another embodiment of the invention, ribozymes or antisensemolecules that cleave target RNA molecules or inhibit the Alzheimer'sdisease related genes identified above are expressed from transcriptionunits inserted into DNA or RNA vectors. Preferably, ribozymes orantisense molecules that cleave BACE, ps-2, or APP (preferably BACE,ps-2, or APP gene) activity are expressed from transcription unitsinserted into DNA or RNA vectors. The recombinant vectors are preferablyDNA plasmids or viral vectors. Ribozyme or antisense expressing viralvectors can be constructed based on, but not limited to,adeno-associated virus, retrovirus, adenovirus, or alphavirus.Preferably, the recombinant vectors capable of expressing the ribozymesor antisense are delivered as described above, and persist in targetcells. Alternatively, viral vectors may be used that provide fortransient expression of ribozymes or antisense. Such vectors can berepeatedly administered as necessary. Once expressed, the ribozymes orantisense bind to the target RNA and inhibit its function or expression.Delivery of ribozyme or antisense expressing vectors can be systemic,such as by intravenous or intramuscular administration, byadministration to target cells ex-planted from the patient followed byreintroduction into the patient, or by any other means that would allowfor introduction into the desired target cell.

[0193] By “vectors” is meant any nucleic acid- and/or viral-basedtechnique used to deliver a desired nucleic acid.

[0194] By “patient” is meant an organism, which is a donor or recipientof explanted cells or the cells themselves. “Patient” also refers to anorganism to which the nucleic acid molecules of the invention can beadministered. Preferably, a patient is a mammal or mammalian cells. Morepreferably, a patient is a human or human cells.

[0195] The nucleic acid molecules of the instant invention,individually, or in combination or in conjunction with other drugs, canbe used to treat diseases or conditions discussed above. For example, totreat a disease or condition associated with the levels of BACE, thepatient may be treated, or other appropriate cells may be treated, as isevident to those skilled in the art, individually or in combination withone or more drugs under conditions suitable for the treatment.

[0196] In a further embodiment, the described molecules, such asantisense or ribozymes, can be used in combination with other knowntreatments to treat conditions or diseases discussed above. For example,the described molecules could be used in combination with one or moreknown therapeutic agents to treat Alzheimer's disease and dementia.

[0197] In another embodiment, the invention features nucleic acid-basedinhibitors (e.g., enzymatic nucleic acid molecules (ribozymes),antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisensenucleic acids containing RNA cleaving chemical groups) and methods fortheir use to down regulate or inhibit the expression of genes (e.g.,BACE) capable of progression and/or maintenance of Alzheimer's disease.

[0198] In one embodiment, the invention features nucleic acid-basedtechniques (e.g., enzymatic nucleic acid molecules (ribozymes),antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisensenucleic acids containing RNA cleaving chemical groups) and methods fortheir use to down regulate or inhibit the expression of BACE, ps-2, orAPP gene expression.

[0199] By “comprising” is meant including, but not limited to, whateverfollows the word “comprising”. Thus, use of the term “comprising”indicates that the listed elements are required or mandatory, but thatother elements are optional and may or may not be present. By“consisting of” is meant including, and limited to, whatever follows thephrase “consisting of”. Thus, the phrase “consisting of” indicates thatthe listed elements are required or mandatory, and that no otherelements may be present. By “consisting essentially of” is meantincluding any elements listed after the phrase, and limited to otherelements that do not interfere with or contribute to the activity oraction specified in the disclosure for the listed elements. Thus, thephrase “consisting essentially of” indicates that the listed elementsare required or mandatory, but that other elements are optional and mayor may not be present depending upon whether or not they affect theactivity or action of the listed elements.

[0200] Other features and advantages of the invention will be apparentfrom the following description of the preferred embodiments thereof, andfrom the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0201]FIG. 1 shows the secondary structure model for seven differentclasses of enzymatic nucleic acid molecules. Arrow indicates the site ofcleavage. --------- indicate the target sequence. Lines interspersedwith dots are meant to indicate tertiary interactions. - is meant toindicate base-paired interaction. Group I Intron: P1-P9.0 representvarious stem-loop structures (Cech et al., 1994, Nature Struc. Bio., 1,273). RNase P (M1RNA): EGS represents external guide sequence (Forsteret al., 1990, Science, 249, 783; Pace et al., 1990, J Biol. Chem., 265,3587). Group II Intron: 5′SS means 5′ splice site; 3′SS means 3′-splicesite; IBS means intron binding site; EBS means exon binding site (Pyleet al., 1994, Biochemistry, 33, 2716). VS RNA: I-VI are meant toindicate six stem-loop structures; shaded regions are meant to indicatetertiary interaction (Collins, International PCT Publication No. WO96/19577). HDV Ribozyme: : I-IV are meant to indicate four stem-loopstructures (Been et al., U.S. Pat. No. 5,625,047). Hammerhead Ribozyme:I-III are meant to indicate three stem-loop structures; stems I-III canbe of any length and may be symmetrical or asymmetrical (Usman et al.,1996, Curr. Op. Struct. Bio., 1, 527). Hairpin Ribozyme: Helix 1, 4 and5 can be of any length; Helix 2 is between 3 and 8 base-pairs long; Y isa pyrimidine; Helix 2 (H2) is provided with a least 4 base pairs (i.e.,n is 1, 2, 3 or 4) and helix 5 can be optionally provided of length 2 ormore bases (preferably 3-20 bases, i.e., m is from 1-20 or more). Helix2 and helix 5 may be covalently linked by one or more bases (i.e., r is≧1 base). Helix 1, 4 or 5 may also be extended by 2 or more base pairs(e.g., 4-20 base pairs) to stabilize the ribozyme structure, andpreferably is a protein binding site. In each instance, each N and N′independently is any normal or modified base and each dash represents apotential base-pairing interaction. These nucleotides may be modified atthe sugar, base or phosphate. Complete base-pairing is not required inthe helices, but is preferred. Helix 1 and 4 can be of any size (i.e., oand p is each independently from 0 to any number, e.g., 20) as long assome base-pairing is maintained. Essential bases are shown as specificbases in the structure, but those in the art will recognize that one ormore may be modified chemically (abasic, base, sugar and/or phosphatemodifications) or replaced with another base without significant effect.Helix 4 can be formed from two separate molecules, i.e., without aconnecting loop. The connecting loop when present may be aribonucleotide with or without modifications to its base, sugar orphosphate. “q” ≧is 2 bases. The connecting loop can also be replacedwith a non-nucleotide linker molecule. H refers to bases A, U, or C. Yrefers to pyrimidine bases. (Burke et al., 1996, Nucleic Acids & Mol.Biol., 10, 129; Chowrira et al., U.S. Pat. No. 5,631,359).

[0202]FIG. 2 shows examples of chemically stabilized ribozyme motifs. HHRz, represents hammerhead ribozyme motif (Usman et al., 1996, Curr. Op.Struct. Bio., 1, 527); NCH Rz represents the NCH ribozyme motif (Ludwig& Sproat, International PCT Publication No. WO 98/58058); G-Cleaver,represents G-cleaver ribozyme motif (Kore et al., 1998, Nucleic AcidsResearch 26, 4116-4120). N or n, represent independently a nucleotidewhich may be same or different and have complementarity to each other;rI, represents ribo-Inosine nucleotide; arrow indicates the site ofcleavage within the target. Position 4 of the HH Rz and the NCH Rz isshown as having 2′-C-allyl modification, but those skilled in the artwill recognize that this position can be modified with othermodifications well known in the art, so long as such modifications donot significantly inhibit the activity of the ribozyme.

[0203]FIG. 3 shows an example of the Amberzyme ribozyme motif that ischemically stabilized (see for example Beigelman et al., U.S. Ser. No.09/301,511, incorporated by reference herein; also referred to as ClassI Motif).

[0204]FIG. 4 shows an example of the Zinzyme ribozyme motif that ischemically stabilized (see for example Beigelman et al., U.S. Ser. No.09/301,511, incorporated by reference herein; also referred to as ClassA or Class II Motif).

[0205]FIG. 5 shows an example of a DNAzyme motif described by Santoro etal., 1997, PNAS, 94, 4262.

[0206]FIG. 6 shows a non-limiting example of a halfzyme enzymaticnucleic acid molecule of the invention. (a) The halfzyme is engineeredby removing a portion of the enzymatic nucleic acid molecule (in thiscase Zinzyme) required for the activity of the enzymatic nucleic acidmolecule. (b) A target molecule is used which allows the halfzyme tobecome active.

[0207]FIG. 7 shows a non-limiting example of a nucleic acid sensormolecule assay of the invention. Interaction of the target molecule withthe sensor portion of the nucleic acid sensor molecule results in theactivation of the nucleic acid sensor molecule. Detection of thechemical reaction catalyzed by the nucleic acid sensor molecule, forexample cleavage of a reporter molecule, provides a signal that can beassayed.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0208] Mechanism of Action of Nucleic Acid Molecules of the Invention

[0209] Antisense:

[0210] Antisense molecules may be modified or unmodified RNA, DNA, ormixed polymer oligonucleotides and primarily function by specificallybinding to matching sequences resulting in inhibition of peptidesynthesis (Wu-Pong, Nov 1994, BioPharm, 20-33). The antisenseoligonucleotide binds to target RNA by Watson Crick base-pairing andblocks gene expression by preventing ribosomal translation of the boundsequences either by steric blocking or by activating RNase H enzyme.Antisense molecules may also alter protein synthesis by interfering withRNA processing or transport from the nucleus into the cytoplasm(Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).

[0211] In addition, binding of single stranded DNA to RNA may result innuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke,supra). To date, the only backbone modified DNA chemistry which will actas substrates for RNase H are phosphorothioates, phosphorodithioates,and borontrifluoridates. Recently it has been reported that 2′-arabinoand 2′-fluoro arabino-containing oligos can also activate RNase Hactivity.

[0212] A number of antisense molecules have been described that utilizenovel configurations of chemically modified nucleotides, secondarystructure, and/or RNase H substrate domains (Woolf et al., InternationalPCT Publication No. WO 98/13526; Thompson et al., U.S. Ser. No.60/082,404 which was filed on Apr. 20, 1998; Hartmann et al., U.S. Ser.No. 60/101,174 which was filed on Sep. 21, 1998) all of these areincorporated by reference herein in their entirety.

[0213] Triplex Forming Oligonucleotides (TFO):

[0214] Single stranded DNA may be designed to bind to genomic DNA in asequence specific manner. TFOs are comprised of pyrimidine-richoligonucleotides which bind DNA helices through Hoogsteen Base-pairing(Wu-Pong, supra). The resulting triple helix composed of the DNA sense,DNA antisense, and TFO disrupts RNA synthesis by RNA polymerase. The TFOmechanism may result in gene expression or cell death since binding maybe irreversible (Mukhopadhyay & Roth, supra)

[0215] 2-5A Antisense Chimera:

[0216] The 2-5A system is an interferon-mediated mechanism for RNAdegradation found in higher vertebrates (Mitra et al., 1996, Proc NatAcad Sci USA 93, 6780-6785). Two types of enzymes, 2-5A synthetase andRNase L, are required for RNA cleavage. The 2-5A synthetases requiredouble stranded RNA to form 2′-5′ oligoadenylates (2-5A). 2-5A then actsas an allosteric effector for utilizing RNase L which has the ability tocleave single stranded RNA. The ability to form 2-5A structures withdouble stranded RNA makes this system particularly useful for inhibitionof viral replication.

[0217] (2′-5′) oligoadenylate structures may be covalently linked toantisense molecules to form chimeric oligonucleotides capable of RNAcleavage (Torrence, supra). These molecules putatively bind and activatea 2-5A dependent RNase, the oligonucleotide/enzyme complex then binds toa target RNA molecule which can then be cleaved by the RNase enzyme.

[0218] Enzymatic Nucleic Acid:

[0219] Seven basic varieties of naturally-occurring enzymatic RNAs arepresently known. In addition, several in vitro selection (evolution)strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have beenused to evolve new nucleic acid catalysts capable of catalyzing cleavageand ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87;Beaudry et al., 1992, Science 257, 635-641; Joyce, 1992, ScientificAmerican 267, 90-97; Breaker et al., 1994, TIBTECH 12, 268; Bartel etal., 1993, Science 261:1411-1418; Szostak, 1993, TIBS 17, 89-93; Kumaret al., 1995, FASEB J, 9, 1183; Breaker, 1996, Curr. Op. Biotech., 7,442; Santoro et al., 1997, Proc. Natl. Acad. Sci., 94, 4262; Tang etal., 1997, RNA 3, 914; Nakamaye & Eckstein, 1994, supra; Long &Uhlenbeck, 1994, supra; Ishizaka et al., 1995, supra; Vaish et al.,1997, Biochemistry 36, 6495; all of these are incorporated by referenceherein). Each can catalyze a series of reactions including thehydrolysis of phosphodiester bonds in trans (and thus can cleave otherRNA molecules) under physiological conditions.

[0220] Nucleic acid molecules of this invention will block to someextent BACE protein expression and can be used to treat disease ordiagnose disease associated with the levels of BACE.

[0221] The enzymatic nature of a ribozyme has significant advantages,such as the concentration of ribozyme necessary to affect a therapeutictreatment is lower. This advantage reflects the ability of the ribozymeto act enzymatically. Thus, a single ribozyme molecule is able to cleavemany molecules of target RNA. In addition, the ribozyme is a highlyspecific inhibitor, with the specificity of inhibition depending notonly on the base-pairing mechanism of binding to the target RNA, butalso on the mechanism of target RNA cleavage. Single mismatches, orbase-substitutions, near the site of cleavage can be chosen tocompletely eliminate catalytic activity of a ribozyme.

[0222] Nucleic acid molecules having an endonuclease enzymatic activityare able to repeatedly cleave other separate RNA molecules in anucleotide base sequence-specific manner. With the proper design, suchenzymatic nucleic acid molecules can be targeted to RNA transcripts, andachieve efficient cleavage in vitro (Zaug et al., 324, Nature 429 1986;Uhlenbeck, 1987 Nature 328, 596; Kim et al., 84 Proc. Natl. Acad. Sci.USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J Bio. Med., 6, 92;Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988;and Jefferies et al., 17 Nucleic Acids Research 1371, 1989; Santoro etal., 1997 supra).

[0223] Because of their sequence specificity, trans-cleaving ribozymesshow promise as therapeutic agents for human disease (Usman & McSwiggen,1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 JMed. Chem. 38, 2023-2037). Ribozymes can be designed to cleave specificRNA targets within the background of cellular RNA. Such a cleavage eventrenders the RNA non-functional and abrogates protein expression fromthat RNA. In this manner, synthesis of a protein associated with adisease state can be selectively inhibited (Warashina et al., 1999,Chemistry and Biology, 6, 237-250.

[0224] Enzymatic nucleic acid molecules of the invention that areallosterically regulated (“allozymes”) can be used to down-regulate theexpression of genes associated with the maintenance and/or progressionof Alzheimer's disease, for example BACE, presenilin-2 (ps-2), oramyloid precursor protein (APP) expression. These allosteric enzymaticnucleic acids or allozymes (see for example George et al., U.S. Pat.Nos. 5,834,186 and 5,741,679, Shih et al., U.S. Pat. No. 5,589,332,Nathan et al, U.S. Pat. No 5,871,914, Nathan and Ellington,International PCT publication No. WO 00/24931, Breaker et al.,International PCT Publication Nos. WO 00/26226 and 98/27104, andSullenger et al., International PCT publication No. WO 99/29842) aredesigned to respond to a signaling agent, for example, mutant BACE,ps-2, or APP protein, wild-type BACE, ps-2, or APP protein, mutant BACE,ps-2, or APP RNA, wild-type BACE, ps-2, or APP RNA, other proteinsand/or RNAs involved in BACE, ps-2, or APP activity, compounds, metals,polymers, molecules and/or drugs that are targeted to BACE, ps-2, or APPexpressing cells etc., which in turn modulates the activity of theenzymatic nucleic acid molecule. In response to interaction with apredetermined signaling agent, the allosteric enzymatic nucleic acidmolecule's activity is activated or inhibited such that the expressionof a particular target is selectively down-regulated. The target cancomprise wild-type BACE, ps-2, or APP, mutant BACE, ps-2, or APP, acomponent of BACE, ps-2, or APP, and/or a predetermined cellularcomponent that modulates BACE, ps-2, or APP activity. In a specificexample, allosteric enzymatic nucleic acid molecules that are activatedby interaction with a RNA encoding BACE, ps-2, or APP protein are usedas therapeutic agents in vivo. The presence of RNA encoding the BACE,ps-2, or APP protein activates the allosteric enzymatic nucleic acidmolecule that subsequently cleaves the RNA encoding BACE, ps-2, or APPprotein resulting in the inhibition of BACE, ps-2, or APP proteinexpression. In this manner, cells that express the BACE, ps-2, or APPprotein are selectively targeted.

[0225] In another non-limiting example, an allozyme can be activated bya BACE, ps-2, or APP protein, peptide, or mutant polypeptide that causedthe allozyme to inhibit the expression of BACE, ps-2, or APP gene, by,for example, cleaving RNA encoded by BACE, ps-2, or APP gene. In thisnon-limiting example, the allozyme acts as a decoy to inhibit thefunction of BACE, ps-2, or APP and also inhibit the expression of BACE,ps-2, or APP once activated by the BACE, ps-2, or APP protein.

[0226] Target Sites

[0227] Targets for useful ribozymes and antisense nucleic acids can bedetermined as disclosed in Draper et al., WO 93/23569; Sullivan et al.,WO 93/23057; Thompson et al., WO 94/02595; Draper et al., WO 95/04818;McSwiggen et al., U.S. Pat. No. 5,525,468, all are hereby incorporatedby reference herein in their totality. Other examples include thefollowing PCT applications, which concern inactivation of expression ofdisease-related genes: WO 95/23225, WO 95/13380, WO 94/02595, allincorporated by reference herein. Rather than repeat the guidanceprovided in those documents here, specific examples of such methods areprovided below, not limiting to those in the art. Ribozymes andantisense to such targets are designed as described in thoseapplications and synthesized, to be tested in vitro and in vivo, as alsodescribed. The sequences of human BACE RNAs were screened for optimalenzymatic nucleic acid and antisense target sites using acomputer-folding algorithm. Antisense, hammerhead, DNAzyme, NCH,amberzyme, zinzyme, or G-Cleaver ribozyme binding/cleavage sites wereidentified. These sites are shown in Tables III to VIII (all sequencesare 5′ to 3′ in the tables; X can be any base-paired sequence, theactual sequence is not relevant here). The nucleotide base position isnoted in the Tables as that site to be cleaved by the designated type ofenzymatic nucleic acid molecule. Thus, the position that is cleaved isfollowing the substrate nucleotide that is written separated from thesequences on either side. For example, in Table m, for Seq. ID No. 1,nucleotide position 9 is the central “C”, and cleavage occurs at orfollowing that nucleotide. While human sequences can be screened andenzymatic nucleic acid molecule and/or antisense thereafter designed, asdiscussed in Stinchcomb et al., WO 95/23225, mouse targeted ribozymesmay be useful to test efficacy of action of the enzymatic nucleic acidmolecule and/or antisense prior to testing in humans.

[0228] Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme orG-Cleaver ribozyme binding/cleavage sites were identified. The nucleicacid molecules were individually analyzed by computer folding (Jaeger etal., 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether thesequences fold into the appropriate secondary structure. Those nucleicacid molecules with unfavorable intramolecular interactions such asbetween the binding arms and the catalytic core were eliminated fromconsideration. Varying binding arm lengths can be chosen to optimizeactivity.

[0229] Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme orG-Cleaver ribozyme binding/cleavage sites were identified and weredesigned to anneal to various sites in the RNA target. The binding armsare complementary to the target site sequences described above. Thenucleic acid molecules were chemically synthesized. The method ofsynthesis used follows the procedure for normal DNA/RNA synthesis asdescribed below and in Usman et al., 1987 J Am. Chem. Soc., 109, 7845;Scaringe et al., 1990 Nucleic Acids Res., 18, 5433; and Wincott et al.,1995 Nucleic Acids Res. 23, 2677-2684; Caruthers et al., 1992, Methodsin Enzymology 211,3-19.

[0230] Synthesis of Nucleic Acid Molecules

[0231] Synthesis of nucleic acids greater than 100 nucleotides in lengthis difficult using automated methods, and the therapeutic cost of suchmolecules is prohibitive. In this invention, small nucleic acid motifs(“small refers to nucleic acid motifs no more than 100 nucleotides inlength, preferably no more than 80 nucleotides in length, and mostpreferably no more than 50 nucleotides in length; e.g., antisenseoligonucleotides, hammerhead or the hairpin ribozymes) are preferablyused for exogenous delivery. The simple structure of these moleculesincreases the ability of the nucleic acid to invade targeted regions ofRNA structure. Exemplary molecules of the instant invention werechemically synthesized, and others can similarly be synthesized.Oligodeoxyribonucleotides were synthesized using standard protocols asdescribed in Caruthers et al., 1992, Methods in Enzymology 211, 3-19,and is incorporated herein by reference.

[0232] The method of synthesis used for normal RNA, including certainenzymatic nucleic acid molecules, follows the procedure as described inUsman et al., 1987, J Am. Chem. Soc., 109, 7845; Scaringe et al., 1990,Nucleic Acids Res., 18, 5433; Wincott et al., 1995, Nucleic Acids Res.23, 2677-2684; and Wincott et al., 1997, Methods Mol. Bio., 74, 59, andmakes use of common nucleic acid protecting and coupling groups, such asdimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In anon-limiting example, small scale syntheses were conducted on a 394Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocolwith a 7.5 min coupling step for alkylsilyl protected nucleotides and a2.5 min coupling step for 2′-O-methylated nucleotides. Table II outlinesthe amounts and the contact times of the reagents used in the synthesiscycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a96-well plate synthesizer, such as the instrument produced by Protogene(Palo Alto, Calif.) with minimal modification to the cycle. A 33-foldexcess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can beused in each coupling cycle of 2′-O-methyl residues relative topolymer-bound 5′-hydroxyl. A 66-fold excess (120 μL of 0.11 M=13.2 μmol)of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess ofS-ethyl tetrazole (120 μL of 0.25 M=30 μmol) can be used in eachcoupling cycle of ribo residues relative to polymer-bound 5′-hydroxyl.Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer,determined by calorimetric quantitation of the trityl fractions, were97.5-99%. Other oligonucleotide synthesis reagents for the 394 AppliedBiosystems, Inc. synthesizer; detritylation solution was 3% TCA inmethylene chloride (ABI); capping was performed with 16% N-methylimidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF(ABI); oxidation solution was 16.9 mM I₂, 49 mM pyridine, 9% water inTHF (PERSEPTIVETM). Burdick & Jackson Synthesis Grade acetonitrile wasused directly from the reagent bottle. S-Ethyltetrazole solution (0.25 Min acetonitrile) was made up from the solid obtained from AmericanInternational Chemical, Inc.

[0233] Deprotection of the RNA was performed using either a two-pot orone-pot protocol. For the two-pot protocol, the polymer-bound trityl-onoligoribonucleotide was transferred to a 4 mL glass screw top vial andsuspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10min. After cooling to −20° C., the supernatant was removed from thepolymer support. The support was washed three times with 1.0 mL ofEtOH:MeCN:H2O/3:1:1, vortexed and the supernatant was then added to thefirst supernatant. The combined supernatants, containing theoligoribonucleotide, were dried to a white powder. The base deprotectedoligoribonucleotide was resuspended in anhydrous TEA/HF/NMP solution(300 μL of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1mL TEA.3HF to provide a 1.4 M HF concentration) and heated to 65° C.After 1.5 h, the oligomer was quenched with 1.5 M NH₄HCO₃.

[0234] Alternatively, for the one-pot protocol, the polymer-boundtrityl-on oligoribonucleotide was transferred to a 4 mL glass screw topvial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1(0.8 mL) at 65° C. for 15 min. The vial was brought to r.t. TEA.3HF (0.1mL) was added and the vial was heated at 65° C. for 15 min. The samplewas cooled at −20° C. and then quenched with 1.5 M NH₄HCO₃.

[0235] For purification of the trityl-on oligomers, the quenched NH₄HCO₃solution was loaded onto a C-18 containing cartridge that had beenprewashed with acetonitrile followed by 50 mM TEAA. After washing theloaded cartridge with water, the RNA was detritylated with 0.5% TFA for13 min. The cartridge was then washed again with water, salt exchangedwith 1 M NaCl and washed with water again. The oligonucleotide was theneluted with 30% acetonitrile.

[0236] Inactive hammerhead ribozymes or binding attenuated control (BAC)oligonucleotides) were synthesized by substituting a U for G5 and a Ufor A₁₄ (numbering from Hertel, K. J., et al., 1992, Nucleic Acids Res.,20, 3252). Similarly, one or more nucleotide substitutions can beintroduced in other enzymatic nucleic acid molecules to inactivate themolecule and such molecules can serve as a negative control.

[0237] The average stepwise coupling yields were >98% (Wincott et al.,1995 Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in theart will recognize that the scale of synthesis can be adapted to belarger or smaller than the example described above, including but notlimited to 96 well format. All that is important is the ratio ofchemicals used in the reaction.

[0238] Alternatively, the nucleic acid molecules of the presentinvention can be synthesized separately and joined togetherpost-synthetically, for example by ligation (Moore et al., 1992, Science256, 9923; Draper et al., International PCT publication No. WO 93/23569;Shabarova et al., 1991, Nucleic Acids Research 19, 4247; Bellon et al.,1997, Nucleosides & Nucleotides, 16, 951; Bellon et al., 1997,Bioconjugate Chem. 8, 204).

[0239] The nucleic acid molecules of the present invention can bemodified extensively to enhance stability by modification with nucleaseresistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro,2′-O-methyl, 2′-H (for a review see Usman and Cedergren, 1992, TIBS 17,34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163). Ribozymes arepurified by gel electrophoresis using general methods or are purified byhigh pressure liquid chromatography (HPLC; See Wincott et al., supra,the totality of which is hereby incorporated herein by reference) andare re-suspended in water.

[0240] The sequences of the ribozymes and antisense constructs that arechemically synthesized, useful in this study, are shown in Tables III toVIII. Those in the art will recognize that these sequences arerepresentative only of many more such sequences where the enzymaticportion of the ribozyme (all but the binding arms) is altered to affectactivity. The ribozyme and antisense construct sequences listed inTables III to VIII may be formed of ribonucleotides or other nucleotidesor non-nucleotides. Such ribozymes with enzymatic activity areequivalent to the ribozymes described specifically in the Tables.Optimizing Activity of the nucleic acid molecule of the invention.

[0241] Chemically synthesizing nucleic acid molecules with modifications(base, sugar and/or phosphate) that prevent their degradation by serumribonucleases may increase their potency (see e.g., Eckstein et al.,International Publication No. WO 92/07065; Perrault et al., 1990 Nature344, 565; Pieken et al., 1991, Science 253, 314; Usman and Cedergren,1992, Trends in Biochem. Sci. 17, 334; Usman et al., InternationalPublication No. WO 93/15187; and Rossi et al., International PublicationNo. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; and Burgin et al.,supra; all of these describe various chemical modifications that can bemade to the base, phosphate and/or sugar moieties of the nucleic acidmolecules herein). All these publications are hereby incorporated byreference herein. Modifications which enhance their efficacy in cells,and removal of bases from nucleic acid molecules to shortenoligonucleotide synthesis times and reduce chemical requirements aredesired.

[0242] There are several examples in the art describing sugar, base andphosphate modifications that can be introduced into nucleic acidmolecules with significant enhancement in their nuclease stability andefficacy. For example, oligonucleotides are modified to enhancestability and/or enhance biological activity by modification withnuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro,2′-O-methyl, 2′-H, nucleotide base modifications (for a review see Usmanand Cedergren, 1992, TIBS. 17, 34; Usman et al., 1994, Nucleic AcidsSymp. Ser. 31, 163; Burgin et al, 1996, Biochemistry, 35, 14090). Sugarmodification of nucleic acid molecules have been extensively describedin the art (see Eckstein et al., International Publication PCT No. WO92/07065; Perrault et al. Nature, 1990, 344, 565-568; Pieken et al.Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem.Sci., 1992, 17, 334-339; Usman et al. International Publication PCT No.WO 93/15187; Sproat, U.S. Pat. No. 5,334,711 and Beigelman et al., 1995,J. Biol. Chem., 270, 25702; Beigelman et al., International PCTpublication No. WO 97/26270; Beigelman et al., U.S. Pat. No. 5,716,824;Usman et al., U.S. Pat. No. 5,627,053; Woolf et al., International PCTPublication No. WO 98/13526; Thompson et al., U.S. Ser. No. 60/082,404which was filed on Apr. 20, 1998; Karpeisky et al., 1998, TetrahedronLett., 39, 1131; Earnshaw and Gait, 1998, Biopolymers (Nucleic acidSciences), 48, 39-55; Verma and Eckstein, 1998, Annu. Rev. Biochem., 67,99-134; and Burlina et al., 1997, Bioorg. Med. Chem., 5, 1999-2010; allof the references are hereby incorporated in their totality by referenceherein). Such publications describe general methods and strategies todetermine the location of incorporation of sugar, base and/or phosphatemodifications and the like into ribozymes without inhibiting catalysis,and are incorporated by reference herein. In view of such teachings,similar modifications can be used as described herein to modify thenucleic acid molecules of the instant invention.

[0243] While chemical modification of oligonucleotide internucleotidelinkages with phosphorothioate, phosphorodithioate, and/or5′-methylphosphonate linkages improves stability, too many of thesemodifications may cause some toxicity. Therefore, when designing nucleicacid molecules, the amount of these internucleotide linkages should beminimized, but can be balanced to provide acceptable stability whilereducing potential toxicity. The reduction in the concentration of theselinkages should lower toxicity resulting in increased efficacy andhigher specificity of these molecules.

[0244] Nucleic acid molecules having chemical modifications whichmaintain or enhance activity are provided. Such nucleic acid is alsogenerally more resistant to nucleases than unmodified nucleic acid.Thus, in a cell and/or in vivo the activity may not be significantlylowered. Therapeutic nucleic acid molecules delivered exogenously mustoptimally be stable within cells until translation of the target RNA hasbeen inhibited long enough to reduce the levels of the undesirableprotein. This period of time varies between hours to days depending uponthe disease state. Clearly, exogenously delivered nucleic acid moleculesshould be resistant to nucleases in order to function as effectiveintracellular therapeutic agents. Improvements in the chemical synthesisof RNA and DNA (see, e.g., Wincott et al., 1995 Nucleic Acids Res. 23,2677; Caruthers et al., 1992, Methods in Enzymology 211,3-19 (allincorporated by reference herein) have expanded the ability to modifynucleic acid molecules by introducing nucleotide modifications toenhance their nuclease stability as described above.

[0245] Use of the nucleic acid-based molecules of the invention willlead to better treatment of disease progression by affording thepossibility of combination therapies (e.g., multiple antisense orenzymatic nucleic acid molecules targeted to different genes, nucleicacid molecules coupled with known small molecule inhibitors, orintermittent treatment with combinations of molecules (includingdifferent motifs) and/or other chemical or biological molecules). Thetreatment of patients with nucleic acid molecules may also includecombinations of different types of nucleic acid molecules.

[0246] By “enhanced enzymatic activity” is meant to include activitymeasured in cells and/or in vivo where the activity is a reflection ofboth catalytic activity and ribozyme stability. In this invention, theproduct of these properties is increased or not significantly (less than10-fold) decreased in vivo compared to an all RNA ribozyme or all DNAenzyme.

[0247] In yet another preferred embodiment, nucleic acid catalystshaving chemical modifications which maintain or enhance enzymaticactivity are provided. Such nucleic acid is also generally moreresistant to nucleases than unmodified nucleic acid. Thus, in a celland/or in vivo the activity may not be significantly lowered. Asexemplified herein, such ribozymes are useful in a cell and/or in vivo,even if activity over all is reduced 10-fold (Burgin et al., 1996,Biochemistry, 35, 14090). Such ribozymes herein are said to “maintain”the enzymatic activity on all RNA ribozyme.

[0248] In another aspect, the nucleic acid molecules comprise a 5′and/or a 3′-cap structure.

[0249] By “cap structure” is meant chemical modifications, which havebeen incorporated at the terminus of the oligonucleotide (see forexample Wincott et al., WO 97/26270, incorporated by reference herein).These terminal modifications protect the nucleic acid molecule fromexonuclease degradation, and may help in delivery and/or localizationwithin a cell. The cap may be present at the 5′-terminus (5′-cap) or atthe 3′-terminus (3′-cap) or may be present on both termini. Innon-limiting examples: the 5′-cap is selected from the group comprisinginverted abasic residue (moiety), 4′,5′-methylene nucleotide;1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide, carbocyclicnucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides;alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage;threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide,3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety;3′-2′-inverted nucleotide moiety; 3′-2′-inverted abasic moiety;1,4-butanediol phosphate; 3′-phosphoramidate; hexylphosphate; aminohexylphosphate; 3′-phosphate; 3′-phosphorothioate; phosphorodithioate; orbridging or non-bridging methylphosphonate moiety (for more details seeBeigelman et al., International PCT publication No. WO 97/26270,incorporated by reference herein). In yet another preferred embodiment,the 3′-cap is selected from a group comprising, 4′,5′-methylenenucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide,carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propylphosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate;1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitolnucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide;phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seconucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentylnucleotide, 5′-5′-inverted nucleotide moiety; 5′-5′-inverted abasicmoiety; 5′-phosphoramidate; 5′-phosphorothioate; 1,4-butanediolphosphate; 5′-amino; bridging and/or non-bridging 5′-phosphoramidate,phosphorothioate and/or phosphorodithioate, bridging or non bridgingmethylphosphonate and 5′-mercapto moieties (for more details seeBeaucage and Iyer, 1993, Tetrahedron 49, 1925; incorporated by referenceherein).

[0250] By the term “non-nucleotide” is meant any group or compound whichcan be incorporated into a nucleic acid chain in the place of one ormore nucleotide units, including either sugar and/or phosphatesubstitutions, and allows the remaining bases to exhibit their enzymaticactivity. The group or compound is abasic in that it does not contain acommonly recognized nucleotide base, such as adenosine, guanine,cytosine, uracil or thymine.

[0251] An “alkyl” group refers to a saturated aliphatic hydrocarbon,including straight-chain, branched-chain, and cyclic alkyl groups.Preferably, the alkyl group has 1 to 12 carbons. More preferably it is alower alkyl of from 1 to 7 carbons, still more preferably 1 to 4carbons. The alkyl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably, hydroxyl, cyano,alkoxy, ═O, ═S, NO₂ or N(CH₃)₂, amino, or SH. The term also includesalkenyl groups which are unsaturated hydrocarbon groups containing atleast one carbon-carbon double bond, including straight-chain,branched-chain, and cyclic groups. Preferably, the alkenyl group has 1to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7carbons, still more preferably 1 to 4 carbons. The alkenyl group may besubstituted or unsubstituted. When substituted the substituted group(s)is preferably, hydroxyl, cyano, alkoxy, ═O, ═S, NO₂, halogen, N(CH₃)₂,amino, or SH. The term “alkyl” also includes alkynyl groups which havean unsaturated hydrocarbon group containing at least one carbon-carbontriple bond, including straight-chain, branched-chain, and cyclicgroups. Preferably, the alkynyl group has 1 to 12 carbons. Morepreferably it is a lower alkynyl of from 1 to 7 carbons, more preferably1 to 4 carbons. The alkynyl group may be substituted or unsubstituted.When substituted the substituted group(s) is preferably, hydroxyl,cyano, alkoxy, ═O, ═S, NO₂ or N(CH₃)₂, amino or SH.

[0252] Such alkyl groups may also include aryl, alkylaryl, carbocyclicaryl, heterocyclic aryl, amide and ester groups. An “aryl” group refersto an aromatic group which has at least one ring having a conjugated pelectron system and includes carbocyclic aryl, heterocyclic aryl andbiaryl groups, all of which may be optionally substituted. The preferredsubstituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH,OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An“alkylaryl” group refers to an alkyl group (as described above)covalently joined to an aryl group (as described above). Carbocyclicaryl groups are groups wherein the ring atoms on the aromatic ring areall carbon atoms. The carbon atoms are optionally substituted.Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms asring atoms in the aromatic ring and the remainder of the ring atoms arecarbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen,and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo,pyrimidyl, pyrazinyl, imidazolyl and the like, all optionallysubstituted. An “amide” refers to an —C(O)—NH—R, where R is eitheralkyl, aryl, alkylaryl or hydrogen. An “ester” refers to an —C(O)—OR′,where R is either alkyl, aryl, alkylaryl or hydrogen.

[0253] By “nucleotide” as used herein is as recognized in the art toinclude natural bases (standard), and modified bases well known in theart. Such bases are generally located at the 1′ position of a nucleotidesugar moiety. Nucleotides generally comprise a base, sugar and aphosphate group. The nucleotides can be unmodified or modified at thesugar, phosphate and/or base moiety, (also referred to interchangeablyas nucleotide analogs, modified nucleotides, non-natural nucleotides,non-standard nucleotides and other; see for example, Usman andMcSwiggen, supra; Eckstein et al., International PCT Publication No. WO92/07065; Usman et al., International PCT Publication No. WO 93/15187;Uhlman & Peyman, supra; all are hereby incorporated by referenceherein). There are several examples of modified nucleic acid bases knownin the art. These have been recently summarized by Limbach et al., 1994,Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of basemodifications that can be introduced into nucleic acid moleculesinclude, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl,pseudouracil, 2,4,6-trimethoxy benzene, 3-methyl uracil, dihydrouridine,naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine),5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g.,5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g.6-methyluridine), propyne, and others (Burgin et al., 1996,Biochemistry, 35, 14090; Uhlman & Peyman, supra). By “modified bases” inthis aspect is meant nucleotide bases other than adenine, guanine,cytosine and uracil at 1′ position or their equivalents; such bases maybe used at any position, for example, within the catalytic core of anenzymatic nucleic acid molecule and/or in the substrate-binding regionsof the nucleic acid molecule.

[0254] By “abasic” is meant sugar moieties lacking a base or havingother chemical groups in place of a base at the 1′ position.

[0255] By “ribonucleotide” is meant a nucleotide with a hydroxyl groupat the 2′ position of a D-ribo-furanose moiety.

[0256] By “unmodified nucleoside” is meant one of the bases adenine,cytosine, guanine, uracil joined to the 1′ carbon of β-D-ribo-furanoseand without substitutions on either moiety.

[0257] By “modified nucleoside” is meant any nucleotide base whichcontains a modification in the chemical structure of an unmodifiednucleotide base, sugar and/or phosphate.

[0258] In connection with 2′-modified nucleotides as described for thepresent invention, by “amino” is meant 2′-NH₂ or 2′-O-NH₂, which may bemodified or unmodified. Such modified groups are described, for example,in Eckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al.,WO 98/28317, respectively, which are both incorporated by reference intheir entireties.

[0259] Various modifications to nucleic acid (e.g., antisense andribozyme) structure can be made to enhance the utility of thesemolecules. Such modifications will enhance shelf-life, half-life invitro, stability, and ease of introduction of such oligonucleotides tothe target site, e.g., to enhance penetration of cellular membranes, andconfer the ability to recognize and bind to targeted cells.

[0260] Use of these molecules will lead to better treatment of diseaseprogression by affording the possibility of combination therapies (e.g.,multiple ribozymes targeted to different genes, ribozymes coupled withknown small molecule inhibitors, or intermittent treatment withcombinations of ribozymes (including different ribozyme motifs) and/orother chemical or biological molecules). The treatment of patients withnucleic acid molecules may also include combinations of different typesof nucleic acid molecules. Therapies may be devised which include amixture of ribozymes (including different ribozyme motifs), antisenseand/or 2-5A chimera molecules to one or more targets to alleviatesymptoms of a disease.

[0261] Administration of Nucleic Acid Molecules

[0262] Methods for the delivery of nucleic acid molecules are describedin Akhtar et al., 1992, Trends Cell Bio., 2, 139; and DeliveryStrategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995,which are both incorporated herein by reference. Sullivan et al., PCT WO94/02595, further describes the general methods for delivery ofenzymatic RNA molecules. These protocols may be utilized for thedelivery of virtually any nucleic acid molecule. Nucleic acid moleculesmay be administered to cells by a variety of methods known to thosefamiliar to the art, including, but not restricted to, encapsulation inliposomes, by iontophoresis, or by incorporation into other vehicles,such as hydrogels, cyclodextrins, biodegradable nanocapsules, andbioadhesive microspheres. For some indications, nucleic acid moleculesmay be directly delivered ex vivo to cells or tissues with or withoutthe aforementioned vehicles. Alternatively, the nucleic acid/vehiclecombination is locally delivered by direct injection or by use of acatheter, infusion pump or stent. Other routes of delivery include, butare not limited to, intravascular, intramuscular, subcutaneous or jointinjection, aerosol inhalation, oral (tablet or pill form), topical,systemic, ocular, intraperitoneal and/or intrathecal delivery. Moredetailed descriptions of nucleic acid delivery and administration areprovided in Sullivan et al., supra, Draper et al., PCT WO93/23569,Beigelman et al., PCT WO99/05094, and Klimuk et al., PCT WO99/04819 allof which have been incorporated by reference herein.

[0263] The molecules of the instant invention can be used aspharmaceutical agents. Pharmaceutical agents prevent, inhibit theoccurrence, or treat (alleviate a symptom to some extent, preferably allof the symptoms) of a disease state in a patient.

[0264] The negatively charged polynucleotides of the invention can beadministered (e.g., RNA, DNA or protein) and introduced into a patientby any standard means, with or without stabilizers, buffers, and thelike, to form a pharmaceutical composition. When it is desired to use aliposome delivery mechanism, standard protocols for formation ofliposomes can be followed. The compositions of the present invention mayalso be formulated and used as tablets, capsules or elixirs for oraladministration; suppositories for rectal administration; sterilesolutions; suspensions for injectable administration; and the like.

[0265] The present invention also includes pharmaceutically acceptableformulations of the compounds described. These formulations includesalts of the above compounds, e.g., acid addition salts, for example,salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonicacid.

[0266] A pharmacological composition or formulation refers to acomposition or formulation in a form suitable for administration, e.g.,systemic administration, into a cell or patient, preferably a human.Suitable forms, in part, depend upon the use or the route of entry, forexample oral, transdermal, or by injection. Such forms should notprevent the composition or formulation to reach a target cell (i.e., acell to which the negatively charged polymer is desired to be deliveredto). For example, pharmacological compositions injected into the bloodstream should be soluble. Other factors are known in the art, andinclude considerations such as toxicity and forms which prevent thecomposition or formulation from exerting its effect.

[0267] By pharmaceutically acceptable formulation is meant, acomposition or formulation that allows for the effective distribution ofthe nucleic acid molecules of the instant invention in the physicallocation most suitable for their desired activity. Nonlimiting examplesof agents suitable for formulation with the nucleic acid molecules ofthe instant invention include: P-glycoprotein inhibitors (such asPluronic P85) which can enhance entry of drugs into the CNS(Jolliet-Riant and Tillement, 1999, Fundam. Clin. Pharmacol., 13,16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide)microspheres for sustained release delivery after intracerebralimplantation (Emerich, D F et al, 1999, Cell Transplant, 8, 47-58)Alkermes, Inc. Cambridge, Mass.; and loaded nanoparticles, such as thosemade of polybutylcyanoacrylate, which can deliver drugs across the bloodbrain barrier and can alter neuronal uptake mechanisms (ProgNeuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). Othernon-limiting examples of delivery strategies for the nucleic acidmolecules of the instant invention include materials described in Boadoet al., 1998, J. Pharm. Sci., 87, 1308-1315; Tyler et al., 1999, FEBSLett., 421, 280-284; Pardridge et al., 1995, PNAS USA., 92, 5592-5596;Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada etal., 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al., 1999,PNAS USA., 96, 7053-7058.

[0268] The invention also features the use compositions comprisingsurface-modified liposomes containing poly (ethylene glycol) lipids(PEG-modified, or long-circulating liposomes or stealth liposomes).These formulations offer a method for increasing the accumulation ofdrugs in target tissues. This class of drug carriers resistsopsonization and elimination by the mononuclear phagocytic system (MPSor RES), thereby enabling longer blood circulation times and enhancedtissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995,95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull. 1995, 43, 1005-1011).Such liposomes have been shown to accumulate selectively in tumors,presumably by extravasation and capture in the neovascularized targettissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995,Biochim. Biophys. Acta, 1238, 86-90). The long-circulating liposomesenhance the pharmacokinetics and pharmacodynamics of DNA and RNA,particularly compared to conventional cationic liposomes which are knownto accumulate in tissues of the MPS (Liu et al., J. Biol. Chem. 1995,42, 24864-24870; Choi et al., International PCT Publication No. WO96/10391; Ansell et al., International PCT Publication No. WO 96/10390;Holland et al., International PCT Publication No. WO 96/10392; all ofthese are incorporated by reference herein). Long-circulating liposomesare also likely to protect drugs from nuclease degradation to a greaterextent compared to cationic liposomes, based on their ability to avoidaccumulation in metabolically aggressive MPS tissues such as the liverand spleen. All of these references are incorporated by referenceherein.

[0269] The present invention also includes compositions prepared forstorage or administration which include a pharmaceutically effectiveamount of the desired compounds in a pharmaceutically acceptable carrieror diluent. Acceptable carriers or diluents for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985) hereby incorporated by reference herein. For example,preservatives, stabilizers, dyes and flavoring agents may be provided.These include sodium benzoate, sorbic acid and esters ofp-hydroxybenzoic acid. In addition, antioxidants and suspending agentsmay be used.

[0270] A pharmaceutically effective dose is that dose required toprevent, inhibit the occurrence, or treat (alleviate a symptom to someextent, preferably all of the symptoms) of a disease state. Thepharmaceutically effective dose depends on the type of disease, thecomposition used, the route of administration, the type of mammal beingtreated, the physical characteristics of the specific mammal underconsideration, concurrent medication, and other factors which thoseskilled in the medical arts will recognize. Generally, an amount between0.1 mg/kg and 100 mg/kg body weight/day of active ingredients isadministered dependent upon potency of the negatively charged polymer.

[0271] The nucleic acid molecules of the present invention may also beadministered to a patient in combination with other therapeuticcompounds to increase the overall therapeutic effect. The use ofmultiple compounds to treat an indication may increase the beneficialeffects while reducing the presence of side effects.

[0272] Alternatively, certain of the nucleic acid molecules of theinstant invention can be expressed within cells from eukaryoticpromoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarryand Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon etal., 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet etal., 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al., 1992, J.Virol., 66, 1432-41; Weerasinghe et al., 1991, J. Virol., 65, 5531-4;Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen etal., 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990 Science,247, 1222-1225; Thompson et al., 1995, Nucleic Acids Res., 23, 2259;Good et al., 1997, Gene Therapy, 4, 45; all which are herebyincorporated by reference herein in their totalities). Those skilled inthe art realize that any nucleic acid can be expressed in eukaryoticcells from the appropriate DNA/RNA vector. The activity of such nucleicacids can be augmented by their release from the primary transcript by aribozyme (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO94/02595; Ohkawa et al., 1992, Nucleic Acids Symp. Ser., 27, 15-6; Tairaet al., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993,Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994, J. Biol. Chem.,269, 25856; all which are hereby incorporated by reference herein intheir totalities).

[0273] In another aspect of the invention, RNA molecules of the presentinvention are preferably expressed from transcription units (see, forexample, Couture et al., 1996, TIG., 12, 510) inserted into DNA or RNAvectors. The recombinant vectors are preferably DNA plasmids or viralvectors. Ribozyme expressing viral vectors could be constructed basedon, but not limited to, adeno-associated virus, retrovirus, adenovirus,or alphavirus. Preferably, the recombinant vectors capable of expressingthe nucleic acid molecules are delivered as described above, and persistin target cells. Alternatively, viral vectors may be used that providefor transient expression of nucleic acid molecules. Such vectors mightbe repeatedly administered as necessary. Once expressed, the nucleicacid molecule binds to the target mRNA. Delivery of nucleic acidmolecule expressing vectors could be systemic, such as by intravenous orintramuscular administration, by administration to target cellsex-planted from the patient followed by reintroduction into the patient,or by any other means that would allow for introduction into the desiredtarget cell (for a review see Couture et al., 1996, TIG., 12, 510).

[0274] In one aspect the invention features an expression vectorcomprising nucleic acid sequence encoding at least one of the nucleicacid molecules of the instant invention. The nucleic acid sequenceencoding the nucleic acid molecule of the instant invention is operablelinked in a manner which allows expression of that nucleic acidmolecule.

[0275] In another aspect the invention features, an expression vectorcomprising: a transcription initiation region (e.g., eukaryotic pol I,II or III initiation region); b) a transcription termination region(e.g. eukaryotic pol I, II or III termination region); c) a nucleic acidsequence encoding at least one of the nucleic acid catalyst of theinstant invention; and wherein said sequence is operably linked to saidinitiation region and said termination region, in a manner which allowsexpression and/or delivery of said nucleic acid molecule. The vector mayoptionally include an open reading frame (ORF) for a protein operablylinked on the 5′ side or the 3′-side of the gene encoding the nucleicacid catalyst of the invention; and/or an intron (interveningsequences).

[0276] Transcription of the nucleic acid molecule sequences are drivenfrom a promoter for eukaryotic RNA polymerase I (pol I), RNA polymeraseII (pol II), or RNA polymerase III (pol III). Transcripts from pol II orpol III promoters will be expressed at high levels in all cells; thelevels of a given pol II promoter in a given cell type will depend onthe nature of the gene regulatory sequences (enhancers, silencers, etc.)present nearby. Prokaryotic RNA polymerase promoters are also used,providing that the prokaryotic RNA polymerase enzyme is expressed in theappropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. US A, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res., 21, 2867-72;Lieber et al., 1993, Methods Enzymol., 217, 47-66; Zhou et al., 1990,Mol. Cell. Biol., 10, 4529-37). Several investigators have demonstratedthat nucleic acid molecules, such as ribozymes expressed from suchpromoters can function in mammalian cells (e.g., Kashani-Sabet et al.,1992, Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992, Proc. Natl.Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20,4581-9; Yu et al., 1993, Proc. Natl. Acad. Sci. U S A, 90, 6340-4;L'Huillier et al., 1992, EMBO J, 11, 4411-8; Lisziewicz et al., 1993,Proc. Natl. Acad. Sci. U. S. A, 90, 8000-4; Thompson et al, 1995,Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262,1566). More specifically, transcription units such as the ones derivedfrom genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) andadenovirus VA RNA are useful in generating high concentrations ofdesired RNA molecules such as ribozymes in cells (Thompson et al.,supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994,Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803;Good et al., 1997, Gene Ther., 4, 45; Beigelman et al., InternationalPCT Publication No. WO 96/18736; all of these publications areincorporated by reference herein. The above ribozyme transcription unitscan be incorporated into a variety of vectors for introduction intomammalian cells, including but not restricted to, plasmid DNA vectors,viral DNA vectors (such as adenovirus or adeno-associated virusvectors), or viral RNA vectors (such as retroviral or alphavirusvectors) (for a review see Couture and Stinchcomb, 1996, supra).

[0277] In yet another aspect, the invention features an expressionvector comprising nucleic acid sequence encoding at least one of thenucleic acid molecules of the invention, in a manner which allowsexpression of that nucleic acid molecule. The expression vectorcomprises in one embodiment; a) a transcription initiation region; b) atranscription termination region; c) a nucleic acid sequence encoding atleast one said nucleic acid molecule; and wherein said sequence isoperably linked to said initiation region and said termination region,in a manner which allows expression and/or delivery of said nucleic acidmolecule. In another preferred embodiment, the expression vectorcomprises: a) a transcription initiation region; b) a transcriptiontermination region; c) an open reading frame; d) a nucleic acid sequenceencoding at least one said nucleic acid molecule, wherein said sequenceis operably linked to the 3′-end of said open reading frame; and whereinsaid sequence is operably linked to said initiation region, said openreading frame and said termination region, in a manner which allowsexpression and/or delivery of said nucleic acid molecule. In yet anotherembodiment, the expression vector comprises: a) a transcriptioninitiation region; b) a transcription termination region; c) an intron;d) a gene encoding at least one said nucleic acid molecule; and whereinsaid gene is operably linked to said initiation region, said intron andsaid termination region, in a manner which allows expression and/ordelivery of said nucleic acid molecule. In another embodiment, theexpression vector comprises: a) a transcription initiation region; b) atranscription termination region; c) an intron; d) an open readingframe; e) a nucleic acid sequence encoding at least one said nucleicacid molecule, wherein said sequence is operably linked to the 3′-end ofsaid open reading frame; and wherein said sequence is operably linked tosaid initiation region, said intron, said open reading frame and saidtermination region, in a manner which allows expression and/or deliveryof said nucleic acid molecule.

EXAMPLES

[0278] The following are non-limiting examples showing the selection,isolation, synthesis and activity of nucleic acids of the instantinvention.

[0279] The following examples demonstrate the selection and design ofantisense, hammerhead, DNAzyme, NCH, or G-Cleaver ribozyme molecules andbinding/cleavage sites within BACE RNA.

Example 1 Identification of Potential Target Sites in Human BACE RNA

[0280] The sequence of human BACE was screened for accessible sitesusing a computer-folding algorithm. Regions of the RNA that did not formsecondary folding structures and contained potential ribozyme and/orantisense binding/cleavage sites were identified. The sequences of thesecleavage sites are shown in Tables III-VIII.

Example 2 Selection of Enzymatic Nucleic Acid Cleavage Sites in HumanBACE RNA

[0281] Ribozyme target sites were chosen by analyzing sequences of HumanBACE (Genbank sequence accession number: AF190725) and prioritizing thesites on the basis of folding. Ribozymes were designed that could bindeach target and were individually analyzed by computer folding(Christoffersen et al., 1994 J. Mol. Struc. Theochem, 311, 273; Jaegeret al., 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whetherthe ribozyme sequences fold into the appropriate secondary structure.Those ribozymes with unfavorable intramolecular interactions between thebinding arms and the catalytic core were eliminated from consideration.As noted below, varying binding arm lengths can be chosen to optimizeactivity. Generally, at least 5 bases on each arm are able to bind to,or otherwise interact with, the target RNA.

Example 3 Chemical Synthesis and Purification of Ribozymes and Antisensefor Efficient Cleavage and/or Blocking of BACE RNA

[0282] Ribozymes and antisense constructs were designed to anneal tovarious sites in the RNA message. The binding arms of the ribozymes arecomplementary to the target site sequences described above, while theantisense constructs are filly complimentary to the target sitesequences described above. The ribozymes and antisense constructs werechemically synthesized. The method of synthesis used followed theprocedure for normal RNA synthesis as described above and in Usman etal., (1987 J. Am. Chem. Soc., 109, 7845), Scaringe et al., (1990 NucleicAcids Res., 18, 5433) and Wincott et al., supra, and made use of commonnucleic acid protecting and coupling groups, such as dimethoxytrityl atthe 5′-end, and phosphoramidites at the 3′-end. The average stepwisecoupling yields were >98%.

[0283] Ribozymes and antisense constructs were also synthesized from DNAtemplates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck,1989, Methods Enzymol. 180, 51). Ribozymes and antisense constructs werepurified by gel electrophoresis using general methods or were purifiedby high pressure liquid chromatography (HPLC; See Wincott et al., supra;the totality of which is hereby incorporated herein by reference) andwere resuspended in water. The sequences of the chemically synthesizedribozymes and antisense constructs used in this study are shown below inTable III-VIII.

Example 4 Ribozyme Cleavage of BACE RNA Target in vitro

[0284] Ribozymes targeted to the human BACE RNA are designed andsynthesized as described above. These ribozymes can be tested forcleavage activity in vitro, for example, using the following procedure.The target sequences and the nucleotide location within the BACE RNA aregiven in Tables III-VIII.

[0285] Cleavage Reactions:

[0286] Full-length or partially full-length, internally-labeled targetRNA for ribozyme cleavage assay is prepared by in vitro transcription inthe presence of [a-³²P] CTP, passed over a G 50 Sephadex column by spinchromatography and used as substrate RNA without further purification.Alternately, substrates are 5′-³²P-end labeled using T4 polynucleotidekinase enzyme. Assays are performed by pre-warming a 2× concentration ofpurified ribozyme in ribozyme cleavage buffer (50 mM Tris-HCl, pH 7.5 at37° C., 10 mM MgCl₂) and the cleavage reaction was initiated by addingthe 2× ribozyme mix to an equal volume of substrate RNA (maximum of 1-5nM) that was also pre-warmed in cleavage buffer. As an initial screen,assays are carried out for 1 hour at 37° C. using a final concentrationof either 40 nM or 1 mM ribozyme, i.e., ribozyme excess. The reaction isquenched by the addition of an equal volume of 95% formamide, 20 mMEDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which thesample is heated to 95° C. for 2 minutes, quick chilled and loaded ontoa denaturing polyacrylamide gel. Substrate RNA and the specific RNAcleavage products generated by ribozyme cleavage are visualized on anautoradiograph of the gel. The percentage of cleavage is determined byPhosphor Imager® quantitation of bands representing the intact substrateand the cleavage products.

Example 5 Protein (APP/BACE/ps-2) Target Activation of Nucleic AcidSensor Molecule

[0287] One method for protein detection contemplated by the inventionutilizes a catalytically attenuated enzymatic nucleic acid molecule thatis fused to a high affinity RNA ligand for a target protein in such away that target association induces catalytic activity. A variation ofcombinatorial selection methods can be easily and quickly used to createhigh affinity RNA ligands (RNA sensor domains) for specific proteins.Combinatorial selection of RNA aptamers has been automated andmultiplexed, providing a high throughput method for their production. Aswith antibodies, RNA aptamers display picomolar affinities for theirtargets and can discriminate between protein homologs, isoforms, andeven different activation states of the same protein. Alternately, RNAsensor domains can be obtained from natural sources, such as the RNAbinding domains of a virus (e.g. rev response elements and TAR elementsof HIV) or eukaryotic RNA binding proteins (e.g. protein kinase PKR,promoters, RNA polymerase, ribosomal RNA binding domains etc). Inaddition, a random sequence can be attached to an attenuated enzymaticnucleic acid molecule and through the use of combinatorial selection,allosteric nucleic acid molecules can be isolated that are modulated inthe presence of a target signaling agent or molecule.

[0288] This approach relies upon binding of a protein target to an RNAaptamer domain in the nucleic acid sensor molecule to induce catalyticactivity. To accomplish this activation, the sensor and enzymaticnucleic acid molecule domains are fused via a third element, acommunication module, that is responsible promoting enzymatic nucleicacid molecule catalysis upon target binding. The communication module isa nucleic acid sequence or sequences that promote a conformationalrearrangement of the enzymatic nucleic acid molecule domain into itsactive structure upon target binding. Two routes exist for theproduction of communication modules: rational design or combinatorialselection. One approach utilizes rational design where pre-madecommunication module or modules are fused to preexisting enzymaticnucleic acid molecule and aptamer domains in a modular strategy.

[0289] An RNA sensor domain that binds to BACE, ps-2, or APP protein isappended to a variant of the hammerhead enzymatic nucleic acid moleculethrough a communication module developed through rational design. Thesalient feature of this design strategy is that substrate-bindingelements in the enzymatic nucleic acid molecule domain are sequesteredby complementary allosteric effector sequences present in thecommunication module in the absence of target. Target association withthe sensor domain forces an alternative RNA conformation in which thesubstrate binding elements become available for interaction withcleavage substrate, thus promoting catalysis.

[0290] This nucleic acid sensor displays little catalytic activity inthe absence of the BACE, ps-2, or APP protein but is activated in thepresence of recombinant protien. No nucleic acid sensor activation isobserved if another protein, for example bovine serum albumin (BSA),replaces BACE, ps-2, or APP in the reaction, indicating that activationspecifically requires BACE, ps-2, or APP. An enzymatic nucleic acidmolecule that does not contain the BACE, ps-2, or APP sensor componentdisplays nearly identical activity in the presence or absence of theprotein target. To examine the dependence of activation on theconcentration of BACE, ps-2, or APP, various amounts of BACE, ps-2, orAPP are added to different reactions.

[0291] Cell Culture Models

[0292] Vassar et al., 1999, Science, 286, 735-741, describe a cellculture model for studying BACE inhibition. Specific antisense nucleicacid molecules targeting BACE mRNA were used for inhibition studies ofendogenous BACE expression in 101 cells and APPsw (Swedish type amyloidprecursor protein expressing) cells via lipid mediated transfection.Antisense treatment resulted in dramatic reduction of both BACE mRNA byNorthern blot analysis, and APPsβsw (“Swedish” type β-secretase cleavageproduct) by ELISA, with maximum inhibition of both parameters at 75-80%.This model was also used to study the effect of BACE inhibition onamyloid β-peptide production in APPsw cells.

[0293] Animal Models

[0294] Games et al., 1995, Nature, 373, 523-527, describe a transgenicmouse model in which mutant human familial type APP (Phe 717 instead ofVal) is overexpressed. This model results in mice that progressivelydevelop many of the pathological hallmarks of Alzheimer's disease, andas such, provides a model for testing therapeutic drugs.

[0295] Indications

[0296] Particular degenerative and disease states that can be associatedwith BACE, APP, as ps-2 expression modulation include but are notlimited to neurodegenerative diseases such as Alzheimer's disease anddementia.

[0297] The present body of knowledge in BACE, APP, as ps-2 researchindicates the need for methods to assay BACE activity and for compoundsthat can regulate BACE, APP, as ps-2 expression for research,diagnostic, and therapeutic use.

[0298] Donepezil, tacrine, selegeline, and acetyl-L-camitine arenon-limiting examples of pharmaceutical agents that can be combined withor used in conjunction with the nucleic acid molecules (e.g. ribozymesand antisense molecules) of the instant invention. Those skilled in theart will recognize that other drugs such as diuretic andantihypertensive compounds and therapies can be similarly be readilycombined with the nucleic acid molecules of the instant invention (e.g.ribozymes and antisense molecules) are hence within the scope of theinstant invention.

[0299] Diagnostic Uses

[0300] The nucleic acid molecules of this invention (e.g., enzymaticnucleic acid molecules) can be used as diagnostic tools to examinegenetic drift and mutations within diseased cells or to detect thepresence of BACE, PS-2, or APP RNA in a cell. The close relationshipbetween enzymatic nucleic acid molecule activity and the structure ofthe target RNA allows the detection of mutations in any region of themolecule which alters the base-pairing and three-dimensional structureof the target RNA. By using multiple enzymatic nucleic acid moleculesdescribed in this invention, one can map nucleotide changes which areimportant to RNA structure and function in vitro, as well as in cellsand tissues. Cleavage of target RNAs with enzymatic nucleic acidmolecules can be used to inhibit gene expression and define the role(essentially) of specified gene products in the progression of disease.In this manner, other genetic targets can be defined as importantmediators of the disease. These experiments can lead to better treatmentof the disease progression by affording the possibility of combinationaltherapies (e.g., multiple enzymatic nucleic acid molecules targeted todifferent genes, enzymatic nucleic acid molecules coupled with knownsmall molecule inhibitors, or intermittent treatment with combinationsof enzymatic nucleic acid molecules and/or other chemical or biologicalmolecules). Other in vitro uses of enzymatic nucleic acid molecules ofthis invention are well known in the art, and include detection of thepresence of mRNAs associated with BACE, PS-2, or APP-related condition.

[0301] Such RNA is detected by determining the presence of a cleavageproduct after treatment with an enzymatic nucleic acid molecule usingstandard methodology.

[0302] In a specific example, enzymatic nucleic acid molecules whichcleave only wild-type or mutant forms of the target RNA are used for theassay. The first enzymatic nucleic acid molecule is used to identifywild-type RNA present in the sample and the second enzymatic nucleicacid molecule is used to identify mutant RNA in the sample. As reactioncontrols, synthetic substrates of both wild-type and mutant RNA arecleaved by both enzymatic nucleic acid molecules to demonstrate therelative enzymatic nucleic acid molecule efficiencies in the reactionsand the absence of cleavage of the “non-targeted” RNA species. Thecleavage products from the synthetic substrates also serve to generatesize markers for the analysis of wild-type and mutant RNAs in the samplepopulation. Thus each analysis requires two enzymatic nucleic acidmolecules, two substrates and one unknown sample which is combined intosix reactions. The presence of cleavage products is determined using anRNAse protection assay so that full-length and cleavage fragments ofeach RNA can be analyzed in one lane of a polyacrylamide gel. It is notabsolutely required to quantify the results to gain insight into theexpression of mutant RNAs and putative risk of the desired phenotypicchanges in target cells. The expression of mRNA whose protein product isimplicated in the development of the phenotype (i.e., BACE, PS-2, orAPP) is adequate to establish risk. If probes of comparable specificactivity are used for both transcripts, then a qualitative comparison ofRNA levels will be adequate and will decrease the cost of the initialdiagnosis. Higher mutant form to wild-type ratios are correlated withhigher risk whether RNA levels are compared qualitatively orquantitatively. The use of enzymatic nucleic acid molecules indiagnostic applications contemplated by the instant invention isdescribed, for example, in George et al, U.S. Pat. Nos. 5,834,186 and5,741,679, Shih et al., U.S. Pat. No. 5,589,332, Nathan et al., U.S.Pat. No 5,871,914, Nathan and Ellington, International PCT publicationNo. WO 00/24931, Breaker et al., International PCT Publication Nos. WO00/26226 and 98/27104, and Sullenger et al., International PCTpublication No. WO 99/29842.

[0303] Additional Uses

[0304] Potential usefulness of sequence-specific enzymatic nucleic acidmolecules of the instant invention might have many of the sameapplications for the study of RNA that DNA restriction endonucleaseshave for the study of DNA (Nathans et al., 1975 Ann. Rev. Biochem.44:273). For example, the pattern of restriction fragments could be usedto establish sequence relationships between two related RNAs, and largeRNAs could be specifically cleaved to fragments of a size more usefulfor study. The ability to engineer sequence specificity of the enzymaticnucleic acid molecule is ideal for cleavage of RNAs of unknown sequence.Applicant describes the use of nucleic acid molecules to down-regulategene expression of target genes in bacterial, microbial, fungal, viral,and eukaryotic systems including plant, or mammalian cells. TABLE IIIHuman BACE Hammerhead Ribozyme and Target Sequence Pos Substrate Seq IDRibozyme Seq ID 9 CCACGCGU C CGCAGCCC 1 GGGCUGCG CUGAUGAGGCCGUUAGGC CGAA ACGCGUGG 1776 47 AGCUGGAU U AUGCUGGC 2 GCCACCAU CUGAUGAGGCCGUUAGGC CGAA AUCCAGCU 1777 48 GCUGGAUU A UGGUGGCC 3 GGCCACCA CUGAUGAGGCCGUUAGGC CGAA AAUCCAGC 1778 93 GGAGCCCU U GCCCCUGC 4 GCAGGGGC CUGAUGAGGCCGUUAGGC CGAA AGGGCUCC 1779 163 CCGCCCCU C CCAGCCCC 5 GGGGCUGGCUGAUGAG GCCGUUAGGC CGAA AGGGGCGG 1780 221 GCCGAUGU A GCGGGCUC 6GAGCCCGC CUGAUGAG GCCGUUAGGC CGAA ACAUCGGC 1781 229 AGCGGGCU C CGGAUCCC7 GGGAUCCG CUGAUGAG GCCGUUAGGC CGAA AGCCCGCU 1782 235 CUCCGGAU CCCAGCCUC 8 GAGGCUGG CUGAUGAG GCCGUUAGGC CGAA AUCCGGAG 1783 243 CCCAGCCUC UCCCCUGC 9 GCAGGGGA CUGAUGAG GCCGUUAGGC CGAA AGGCUGGG 1784 245CAGCCUCU C CCCUGCUC 10 GAUCAGUG CUGAUGAG GCCGUUAGGC CGAA AGAGGCUG 1785253 CCCCUGCU C CCGUGCUC 11 GAGCACGG CUGAUGAG GCCGUUAGGC CGAA AGCAGGGG1786 261 CCCGUGCU C UGCGGAUC 12 GAUCCGCA CUGAUGAG GCCGUUAGGC CGAAAGCACGGG 1787 269 CUGCGGAU C UCCCCUGA 13 UCAGGUGA CUGAUGAGGCCGUUAGGC CGAA AUCCGCAG 1788 271 GCGGAUCU C CCCUGACC 14 UGUCAGUGCUGAUGAG GCCGUUAGGC CGAA AGAUCCGC 1789 283 UGACCGCU C UCCACAUC 15UCUGUGGA CUGAUGAG GCCGUUAGGC CGAA AGCGGUCA 1790 285 ACCGCUCU C CACAGCCC16 GGGCUGUG CUGAUGAG GCCGUUAGGC CGAA AGAGCGGU 1791 334 CCUGGCGU CCUGAUGCC 17 GUCAUCAG CUGAUGAG GCCGUUAGGC CGAA ACGCCAGG 1792 351 CCCAAGCUC CCUCUCCU 18 AGGAGAUG CUGAUGAG GCCGUUAGGC CGAA AGCUUGGG 1793 355AGCUCCCU C UCCUGAGA 19 UCUCAGGA CUGAUGAG GCCGUUAGGC CGAA AGGGAGCU 1794357 CUCCCUCU C CUGAGAAG 20 CUUCUCAG CUGAUGAG GCCGUUAGGC CGAA AGAGGGAG1795 386 CCCAGACU U GUGGUCAG 21 CUGCCCCC CUGAUGAG GCCGUUAGGC CGAAAGUCUGGG 1796 477 CCCUGUCU C CUGCUGUG 22 CACAGCAG CUGAUGAGGCCGUUAGGC CGAA AGCCAGGG 1797 531 CACGGCAU C CGGCUGCC 23 GGCAGCCGCUGAUGAG GCCGUUAGGC CGAA AUGCCGUG 1798 632 GGGCAGCU U UGUGGAGA 24UCUCCACA CUGAUGAG GCCGUUAGGC CGAA AGCUGCCC 1799 633 GGCAGCUU U GUGGAGAU25 AUCUCCAC CUGAUGAG GCCGUUAGGC CGAA AAGCUGCC 1800 665 GGGCAAGU CUGGUCAUG 26 CCUGCCCC CUGAUGAG GCCGUUAGGC CGAA ACUUGCCC 1801 677 GCAGUUCUA CUACGUGU 27 CCACUUAG CUGAUGAG GCCGUUAGGC CGAA AGCCCUGC 1802 680GGGCUACU A CGUGGAGA 28 UCUCCACG CUGAUGAG GCCGUUAGGC CGAA AGUAGCCC 1803717 CAGACGCU C AACAUCCU 29 AGGAUGUU CUGAUGAG GCCGUUAGGC CGAA AGCGUCUG1804 723 CUCAACAU C CUGGUGGA 30 UCCACCAG CUGAUGAG GCCGUUAGGC CGAAAUGUUGAG 1805 733 UGGUGGAU A CAGGCAGC 31 GCUGCCUG CUGAUGAGGCCGUUAGGC CGAA AUCCACCA 1806 745 GCAGCAGU A ACUUUGCA 32 UGCAAAGUCUGAUGAG GCCGUUAGGC CGAA ACUGCUGC 1807 749 CAGUAACU U UGCAGUGG 33CCACUGCA CUGAUGAG GCCGUUAGGC CGAA AGUUACUG 1808 750 AGUAACUU U GCAGUGGG34 CCCACUGC CUGAUGAG GCCGUUAGGC CGAA AAGUUACU 1809 776 CCACCCCU UCCUGCAUC 35 GAUGCAGG CUGAUGAG GCCGUUAGGC CGAA AGGGGUGG 1810 777 CACCCCUUC CUGCAUCG 36 CGAUGCAG CUGAUGAG GCCGUUAGGC CGAA AAGGGGUG 1811 784UCCUGCAU C GCUACUAC 37 GUAGUAGC CUGAUGAG GCCGUUAGGC CGAA AUGCAGGA 1812788 GCAUCGCU A CUACCAGA 38 UCUGGUAG CUGAUGAG GCCGUUAGGC CGAA AGCGAUGC1813 791 UCGCUACU A CCAGAGGC 39 GCCUCUGG CUGAUGAG GCCGUUAGGC CGAAAGUAGCGA 1814 806 GCAGCUGU C CAGCACAU 40 AUGUGCUG CUGAUGAGGCCGUUAGGC CGAA ACAGCUGC 1815 815 CAGCACAU A CCGGGACC 41 GGUCCCGGCUGAUGAG GCCGUUAGGC CGAA AUGUGCUG 1816 825 CGGGACCU C CGGAAGGG 42CCCUUCCG CUGAUGAG GCCGUUAGGC CGAA AGGUCCCG 1817 839 GGGUGUGU A UGUGCCCU43 AGGGCACA CUGAUGAG GCCGUUAGGC CGAA ACACACCC 1818 848 UGUGCCCU ACACCCAGG 44 CCUGGGUG CUGAUGAG GCCGUUAGGC CGAA AGGGCACA 1819 891 GACCUGGUA AGCAUCCC 45 GGGAUGCU CUGAUGAG GCCGUUAGGC CGAA ACCAGGUC 1820 897GUAAGCAU C CCCCAUGG 46 CCAUGGGG CUGAUGAG GCCGUUAGGC CGAA AUGCUUAC 1821915 CCCAACGU C ACUGUGCG 47 CGCACAGU CUGAUGAG GCCGUUAGGC CGAA ACGUUGGG1822 933 GCCAACAU U GCUGCCAU 48 AUGGCAGC CUGAUGAG GCCGUUAGGC CGAAAUGUUGGC 1823 942 GCUGCCAU C ACUGAAUC 49 GAUUCAGU CUGAUGAGGCCGUUAGGC CGAA AUGGCAGC 1824 950 CACUGAAU C AGACAAGU 50 ACUUGUCUCUGAUGAG GCCGUUAGGC CGAA AUUCAGUG 1825 959 AGACAAGU U CUUCAUCA 51UGAUGAAG CUGAUGAG GCCGUUAGGC CGAA ACUUGUCU 1826 960 GACAAGUU C UUCAUCAA52 UUGAUGAA CUGAUGAG GCCGUUAGGC CGAA AACUUGUC 1827 962 CAAGUUCU UCAUCAACG 53 CGUUGAUG CUGAUGAG GCCGUUAGGC CGAA AGAACUUG 1828 963 AAGUUCUUC AUCAACGG 54 CCGUUGAU CUGAUGAG GCCGUUAGGC CGAA AAGAACUU 1829 966UUCUUCAU C AACGGCUC 55 GAGCCGUU CUGAUGAG GCCGUUAGGC CGAA AUGAAGAA 1830974 CAACGGCU C CAACUGGG 56 CCCAGUUG CUGAUGAG GCCGUUAGGC CGAA AGCCGUUG1831 990 GAAGGCAU C CUGGGGCU 57 AGCCCCAG CUGAUGAG GCCGUUAGGC CGAAAUGCCUUC 1832 1004 GCUGGCCU A UGCUGAGA 58 UCUCAGCA CUGAUGAGGCCGUUAGGC CGAA AGGCCAGC 1833 1014 GCUGAGAU U GCCAGGCC 59 GGCCUGGCCUGAUGAG GCCGUUAGGC CGAA AUCUCAGC 1834 1031 UGACGACU C CCUGGAGC 60GCUCCAGG CUGAUGAG GCCGUUAGGC CGAA AGUCGUCA 1835 1042 UGGAGCCU U UCUUGGAC61 GUCAAAGA CUGAUGAG GCCGUUAGGC CGAA AGGCUCCA 1836 1043 GGAGCCUU UCUUUGACU 62 AGUCAAAG CUGAUGAG GCCGUUAGGC CGAA AAGGCUCC 1837 1044GAGCCUUU C UUUGACUC 63 GAGUCAAA CUGAUGAG GCCGUUAGGC CGAA AAAGGCUC 18381046 GCCUUUCU U UGACUCUC 64 GAGAGUCA CUGAUGAG GCCGUUAGGC CGAA AGAAAGGC1839 1047 CCUUUCUU U GACUCUCU 65 AGAGAGUC CUGAUGAG GCCGUUAGGC CGAAAAGAAGG 1840 1052 CUUUGACU C UCUGGUAA 66 UUACCAGA CUGAUGAGGCCGUUAGGC CGAA AGUCAAAG 1841 1054 UUGACUCU C UGGUAAAG 67 CUUUACCACUGAUGAG GCCGUUAGGC CGAA AGAGUCAA 1842 1059 UCUCUGGU A AAGCAGAC 68GUCUGCUU CUGAUGAG GCCGUUAGGC CGAA ACCAGAGA 1843 1074 ACCCACGU U CCCAACCU69 AGGUUGGG CUGAUGAG GCCGUUAGGC CGAA ACGUGGGU 1844 1075 CCCACGUU CCCAACCUC 70 GAGGUUGG CUGAUGAG GCCGUUAGGC CGAA AACGUGGG 1845 1083CCCAACCU C UUCUCCCU 71 AGGGAGAA CUGAUGAG GCCGUUAGGC CGAA AGGUUGGG 18461085 CAACCUCU U CUCCCUGC 72 GCAGGGAG CUGAUGAG GCCGUUAGGC CGAA AGAGGUUG1847 1086 AACCUCUU C UCCCUGCA 73 UGCAGGGA CUGAUGAG GCCGUUAGGC CGAAAAGAGGUU 1848 1088 CCUCUUCU C CCUGCAGC 74 GCUGCAGG CUGAUGAGGCCGUUAGGC CGAA AGAAGAGG 1849 1098 CUGCAGCU U UGUGGUGC 75 GCACCACACUGAUGAG GCCGUUAGGC CGAA AGCUGCAG 1850 1099 UGCAGCUU U GUGGUGCU 76AGCACCAC CUGAUGAG GCCGUUAGGC CGAA AAGCUGCA 1851 1112 UGCUGGCU U CCCCCUCA77 UGAGGGGG CUGAUGAG GCCGUUAGGC CGAA AGCCAGCA 1852 1113 GCUGGCUU CCCCCUCAA 78 UUGAGGGG CUGAUGAG GCCGUUAGGC CGAA AAGCCAGC 1853 1119UUCCCCCU C AACCAGUC 79 GACUGGUU CUGAUGAG GCCGUUAGGC CGAA AGGGGGAA 18541127 CAACCAGU C UGAAGUGC 80 GCACUUCA CUGAUGAG GCCGUUAGGC CGAA ACUGGUUG1855 1142 GCUGGCCU C UGUCGGAG 81 CUCCGACA CUGAUGAG GCCGUUAGGC CGAAAGGCCAGC 1856 1146 GCCUCUGU C GGAGGGAG 82 CUCCCUCC CUGAUGAGGCCGUUAGGC CGAA ACAGAGGC 1857 1161 AGCAUGAU C AUUGGAGG 83 CCUCCAAUCUGAUGAG GCCGUUAGGC CGAA AUCAUGCU 1858 1164 AUGAUCAU U GGAGGUAU 84AUACCUCC CUGAUGAG GCCGUUAGGC CGAA AUGAUCAU 1859 1171 UUGGAGGU A UCGACCAC85 GUGGUCCA CUGAUGAG GCCGUUAGGC CGAA ACCUCCAA 1860 1173 GGAGGUAU CGACCACUC 86 GAGUGGUC CUGAUGAG GCCGUUAGGC CGAA AUACCUCC 1861 1181CGACCACU C GCUGUACA 87 UGUACAGC CUGAUGAG GCCGUUAGGC CGAA AGUGGUCG 18621187 CUCGCUGU A CACAGGCA 88 UGCCUGUG CUGAUGAG GCCGUUAGGC CGAA ACAGCGAG1863 1198 CAGGCAGU C UCUGGUAU 89 AUACCAGA CUGAUGAG GCCGUUAGGC CGAAACUGCCUG 1864 1200 GGCAGUCU C UGGUAUAC 90 GUAUACCA CUGAUGAGGCCGUUAGGC CGAA AGACUGCC 1865 1205 UCUCUGGU A UACACCCA 91 UGGGUGUACUGAUGAG GCCGUUAGGC CGAA ACCAGAGA 1866 1207 UCUGGUAU A CACCCAUC 92GAUGGGUG CUGAUGAG GCCGUUAGGC CGAA AUACCAGA 1867 1215 ACACCCAU C CGGCGGGA93 UCCCGCCG CUGAUGAG GCCGUUAGGC CGAA AUGGGUGU 1868 1229 GGAGUGGU AUUAUGAGG 94 CCUCAUAA CUGAUGAG GCCGUUAGGC CGAA ACCACUCC 1869 1231AGUGGUAU U AUGAGGUG 95 CACCUCAU CUGAUGAG GCCGUUAGGC CGAA AUACCACU 18701232 GUGGUAUU A UGAGGUGA 96 UCACCUCA CUGAUGAG GCCGUUAGGC CGAA AAUACCAC1871 1242 GAGGUGAU C AUUGUGCG 97 CGCACAAU CUGAUGAG GCCGUUAGGC CGAAAUCACCUC 1872 1245 GUGAUCAU U GUGCGGGU 98 ACCCGCAC CUGAUGAGGCCGUUAGGC CGAA AUGAUCAC 1873 1260 GUGGAGAU C AAUGGACA 99 UGUCCAUUCUGAUGAG GCCGUUAGGC CGAA AUCUCCAC 1874 1273 GACAGGAU C UGAAAAUG 100CAUUUUCA CUGAUGAG GCCGUUAGGC CGAA AUCCUGUC 1875 1295 CAAGGAGU A CAACUAUG101 CAUAGUUG CUGAUGAG GCCGUUAGGC CGAA ACUCCUUG 1876 1301 GUACAACU AUGACAAGA 102 UCUUGUCA CUGAUGAG GCCGUUAGGC CGAA AGUUGUAC 1877 1314AAGAGCAU U GUGGACAG 103 CUGUCCAC CUGAUGAG GCCGUUAGGC CGAA AUGCUCUU 18781338 ACCAACCU U CGUUUGCC 104 GGCAAACG CUGAUGAG GCCGUUAGGC CGAA AGGUUGGU1879 1339 CCAACCUU C GUUUGCCC 105 GGGCAAAC CUGAUGAG GCCGUUAGGC CGAAAAGGUUGG 1880 1342 ACCUUCGU U UGCCCAAG 106 CUUGGGCA CUGAUGAGGCCGUUAGGC CGAA ACGAAGGU 1881 1343 CCUUCGUU U GCCCAAGA 107 UCUUGGGCCUGAUGAG GCCGUUAGGC CGAA AACGAAGG 1882 1358 GAAAGUGU U UGAAGCUG 108CAGCUUCA CUGAUGAG GCCGUUAGGC CGAA ACACUUUC 1883 1359 AAAGUGUU U GAAGCUGC109 GCAGCUUC CUGAUGAG GCCGUUAGGC CGAA AACACUUU 1884 1371 GCUGCAGU CAAAUCCAU 110 AUGGAUUU CUGAUGAG GCCGUUAGGC CGAA ACUGCAGC 1885 1376AGUCAAAU C CAUCAAGG 111 CCUUGAUG CUGAUGAG GCCGUUAGGC CGAA AUUUGACU 18861380 AAAUCCAU C AAGGCAGC 112 GCUGCCUU CUGAUGAG GCCGUUAGGC CGAA AUGGAUUU1887 1391 GGCAGCCU C CUCCACGG 113 CCGUGGAG CUGAUGAG GCCGUUAGGC CGAAAGGCUGCC 1888 1394 AGCCUCCU C CACGGAGA 114 UCUCCGUG CUGAUGAGGCCGUUAGGC CGAA AGGAGGCU 1889 1406 GGAGAAGU U CCCUGAUG 115 CAUCAGGGCUGAUGAG GCCGUUAGGC CGAA ACUUCUCC 1890 1407 GAGAAGUU C CCUGAUGG 116CCAUCAGG CUGAUGAG GCCGUUAGGC CGAA AACUUCUC 1891 1417 CUGAUGGU U UCUGGCUA117 UAGCCAGA CUGAUGAG GCCGUUAGGC CGAA ACCAUCAG 1892 1418 UGAUGGUU UCUGGCUAG 118 CUAGCCAG CUGAUGAG GCCGUUAGGC CGAA AACCAUCA 1893 1419GAUGGUUU C UGGCUAGG 119 CCUAGCCA CUGAUGAG GCCGUUAGGC CGAA AAACCAUC 18941425 UUCUGGCU A GGAGAGCA 120 UGCUCUCC CUGAUGAG GCCGUUAGGC CGAA AGCCAGAA1895 1465 CCACCCCU U GGAACAUU 121 AAUGUUCC CUGAUGAG GCCGUUAGGC CGAAAGGGGUGG 1896 1473 UGGAACAU U UUCCCAGU 122 ACUGGGAA CUGAUGAGGCCGUUAGGC CGAA AUGUUCCA 1897 1474 GGAACAUU U UCCCAGUC 123 GACUGGGACUGAUGAG GCCGUUAGGC CGAA AAUGUUCC 1898 1475 GAACAUUU U CCCAGUCA 124UGACUGGG CUGAUGAG GCCGUUAGGC CGAA AAAUGUUC 1899 1476 AACAUUUU C CCAGUCAU125 AUGACUGG CUGAUGAG GCCGUUAGGC CGAA AAAAUGUU 1900 1482 UUCCCAGU CAUCUCACU 126 AGUGAGAU CUGAUGAG GCCGUUAGGC CGAA ACUGGGAA 1901 1485CCAGUCAU C UCACUCUA 127 UAGAGUGA CUGAUGAG GCCGUUAGGC CGAA AUGACUGG 19021487 AGUCAUCU C ACUCUACC 128 GGUAGAGU CUGAUGAG GCCGUUAGGC CGAA AGAUGACU1903 1491 AUCUCACU C UACCUAAU 129 AUUAGGUA CUGAUGAG GCCGUUAGGC CGAAAGUGAGAU 1904 1493 CUCACUCU A CCUAAUGG 130 CCAUUAGG CUGAUGAGGCCGUUAGGC CGAA AGAGUGAG 1905 1497 CUCUACCU A AUGGGUGA 131 UCACCCAUCUGAUGAG GCCGUUAGGC CGAA AGGUAGAG 1906 1509 GGUGAGGU U ACCAACCA 132UGGUUGGU CUGAUGAG GCCGUUAGGC CGAA ACCUCACC 1907 1510 GUGAGGUU A CCAACCAG133 CUGGUUGG CUGAUGAG GCCGUUAGGC CGAA AACCUCAC 1908 1520 CAACCAGU CCUUCCGCA 134 UGCGGAAG CUGAUGAG GCCGUUAGGC CGAA ACUGGUUG 1909 1523CCAGUCCU U CCGCAUCA 135 UGAUGCGG CUGAUGAG GCCGUUAGGC CGAA AGGACUGG 19101524 CAGUCCUU C CGCAUCAC 136 GUGAUGCG CUGAUGAG GCCGUUAGGC CGAA AAGGACUG1911 1530 UUCCGCAU C ACCAUCCU 137 AGGAUGGU CUGAUGAG GCCGUUAGGC CGAAAUGCGGAA 1912 1536 AUCACCAU C CUUCCGCA 138 UGCGGAAG CUGAUGAGGCCGUUAGGC CGAA AUGGUGAU 1913 1539 ACCAUCCU U CCGCAGCA 139 UGCUGCGGCUGAUGAG GCCGUUAGGC CGAA AGGAUGGU 1914 1540 CCAUCCUU C CGCAGCAA 140UUGCUGCG CUGAUGAG GCCGUUAGGC CGAA AAGGAUGG 1915 1550 GCAGCAAU A CCUGCGGC141 GCCGCAGG CUGAUGAG GCCGUUAGGC CGAA AUUGCUGC 1916 1580 GGCCACGU CCCAAGACG 142 CGUCUUGG CUGAUGAG GCCGUUAGGC CGAA ACGUGGCC 1917 1594ACGACUGU U ACAAGUUU 143 AAACUUGU CUGAUGAG GCCGUUAGGC CGAA ACAGUCGU 19181595 CGACUGUU A CAAGUUUG 144 CAAACUUG CUGAUGAG GCCGUUAGGC CGAA AACAGUCG1919 1601 UUACAAGU U UGCCAUCU 145 AGAUGGCA CUGAUGAG GCCGUUAGGC CGAAACUUGUAA 1920 1602 UACAAGUU U GCCAUCUC 146 GAGAUGGC CUGAUGAGGCCGUUAGGC CGAA AACUUGUA 1921 1608 UUUGCCAU C UCACAGUC 147 GACUGUGACUGAUGAG GCCGUUAGGC CGAA AUGGCAAA 1922 1610 UGCCAUCU C ACAGUCAU 148AUGACUGU CUGAUGAG GCCGUUAGGC CGAA AGAUGGCA 1923 1616 CUCACAGU C AUCCACGG149 CCGUGGAU CUGAUGAG GCCGUUAGGC CGAA ACUGUGAG 1924 1619 ACAGUCAU CCACGGGCA 150 UGCCCGUG CUGAUGAG GCCGUUAGGC CGAA AUGACUGU 1925 1632GGCACUGU U AUGGGAGC 151 GCUCCCAU CUGAUGAG GCCGUUAGGC CGAA ACAGUGCC 19261633 GCACUGUU A UGGGAGCU 152 AGCUCCCA CUGAUGAG GCCGUUAGGC CGAA AACAGUGC1927 1644 GGAGCUGU U AUCAUGGA 153 UCCAUGAU CUGAUGAG GCCGUUAGGC CGAAACAGCUCC 1928 1645 GAGCUGUU A UCAUGGAG 154 CUCCAUGA CUGAUGAGGCCGUUAGGC CGAA AACAGCIC 1929 1647 GCUGUUAU C AUGGAGGG 155 CCCUCCAUCUGAUGAG GCCGUUAGGC CGAA AUAACAGC 1930 1658 GGAGGGCU U CUACGUUG 156CAACGUAG CUGAUGAG GCCGUUAGGC CGAA AGCCCUCC 1931 1659 GAGGGCUU C UACGUUGU157 ACAACGUA CUGAUGAG GCCGUUAGGC CGAA AAGCCCUC 1932 1661 GGGCUUCU ACGUUGUCU 158 AGACAACG CUGAUGAG GCCGUUAGGC CGAA AGAAGCCC 1933 1665UUCUACGU U GUCUUUGA 159 UCAAAGAC CUGAUGAG GCCGUUAGGC CGAA ACGUAGAA 19341668 UACGUUGU C UUUGAUCG 160 CGAUCAAA CUGAUGAG GCCGUUAGGC CGAA ACAACGUA1935 1670 CGUUGUCU U UGAUCGGG 161 CCCGAUCA CUGAUGAG GCCGUUAGGC CGAAAGACAACG 1936 1671 GUUGUCUU U GAUCGGGC 162 GCCCGAUC CUGAUGAGGCCGUUAGGC CGAA AAGACAAC 1937 1675 UCUUUGAU C GGGCCCGA 163 UCGGGCCCCUGAUGAG GCCGUUAGGC CGAA AUCAAAGA 1938 1692 AAACGAAU U GGCUUUGC 164GCAAAGCC CUGAUGAG GCCGUUAGGC CGAA AUUCGUUU 1939 1697 AAUUGGCU U UGCUGUCA165 UGACAGCA CUGAUGAG GCCGUUAGGC CGAA AGCCAAUU 1940 1698 AUUGGCUU UGCUGUCAG 166 CUGACAGC CUGAUGAG GCCGUUAGGC CGAA AAGCCAAU 1941 1704UUUGCUGU C AGCGCUUG 167 CAAGCGCU CUGAUGAG GCCGUUAGGC CGAA ACAGCAAA 19421711 UCAGCGCU U GCCAUGUG 168 CACAUGGC CUGAUGAG GCCGUUAGGC CGAA AGCGCUGA1943 1730 CGAUGAGU U CAGGACGG 169 CCGUCCUG CUGAUGAG GCCGUUAGGC CGAAACUCAUCG 1944 1731 GAUGAGUU C AGGACGGC 170 GCCGUCCU CUGAUGAGGCCGUUAGGC CGAA AACUCAUC 1945 1756 AAGGCCCU U UUGUCACC 171 GGUGACAACUGAUGAG GCCGUUAGGC CGAA AGGGCCUU 1946 1757 AGGCCCUU U UGUCACCU 172AGGUGACA CUGAUGAG GCCGUUAGGC CGAA AAGGGCU 1947 1758 GGCCCUUU U GUCACCUU173 AAGGUGAC CUGAUGAG GCCGUUAGGC CGAA AAAGGGCC 1948 1761 CCUUUUGU CACCUUGGA 174 UCCAAGGU CUGAUGAG GCCGUUAGGC CGAA ACAAAAGG 1949 1766UGUCACCU U GGACAUGG 175 CCAUGUCC CUGAUGAG GCCGUUAGGC CGAA AGGUGACA 19501787 CUGUGGCU A CAACAUUC 176 GAAUGUUG CUGAUGAG GCCGUUAGGC CGAA AGCCACAG1951 1794 UACAACAU U CCACAGAC 177 GUCUGUGG CUGAUGAG GCCGUUAGGC CGAAAUGUUGUA 1952 1795 ACAACAUU C CACAGACA 178 UGUCUGUG CUGAUGAGGCCGUUAGGC CGAA AAUGUUGU 1953 1811 AGAUGAGU C AACCCUCA 179 UGAGGGUUCUGAUGAG GCCGUUAGGC CGAA ACUCAUCU 1954 1818 UCAACCCU C AUGACCAU 180AUGGUCAU CUGAUGAG GCCGUUAGGC CGAA AGGGUUGA 1955 1827 AUGACCAU A GCCUAUGU181 ACAUAGGC CUGAUGAG GCCGUUAGGC CGAA AUGGUCAU 1956 1832 CAUAGCCU AUGUCAUGG 182 CCAUGACA CUGAUGAG GCCGUUAGGC CGAA AGGCUAUG 1957 1836GCCUAUGU C AUGGCUGC 183 GCAGCCAU CUGAUGAG GCCGUUAGGC CGAA ACAUAGGC 19581848 GCUGCCAU C UGCGCCCU 184 AGGGCGCA CUGAUGAG GCCGUUAGGC CGAA AUGGCAGC1959 1857 UGCGCCCU C UUCAUGCU 185 AGCAUGAA CUGAUGAG GCCGUUAGGC CGAAAGGGCGCA 1960 1859 CGCCCUCU U CAUGCUGC 186 GCAGCAUG CUGAUGAGGCCGUUAGGC CGAA AGAGGGCG 1961 1860 GCCCUCUU C AUGCUGCC 187 GGCAGCAUCUGAUGAG GCCGUUAGGC CGAA AAGAGGGC 1962 1872 CUGCCACU C UGCCUCAU 188AUGAGGCA CUGAUGAG GCCGUUAGGC CGAA AGUGGCAG 1963 1878 CUCUGCCU C AUGGUGUG189 CACACCAU CUGAUGAG GCCGUUAGGC CGAA AGGCAGAG 1964 1888 UGGUGUGU CAGUGGCGC 190 GCGCCACU CUGAUGAG GCCGUUAGGC CGAA ACACACCA 1965 1902CGCUGCCU C CGCUGCCU 191 AGGCAGCG CUGAUGAG GCCGUUAGGC CGAA AGGCAGCG 19661931 UGAUGACU U UGCUGAUG 192 CAUCAGCA CUGAUGAG GCCGUUAGGC CGAA AGUCAUCA1967 1932 GAUGACUU U GCUGAUGA 193 UCAUCAGC CUGAUGAG GCCGUUAGGC CGAAAAGUCAUC 1968 1944 GAUGACAU C UCCCUGCU 194 AGCAGGGA CUGAUGAGGCCGUUAGGC CGAA AUGUCAUC 1969 1946 UGACAUCU C CCUGCUGA 195 UCAGCAGGCUGAUGAG GCCGUUAGGC CGAA AGAUGUCA 1970 1981 CAGAAGAU A GAGAUUCC 196GGAAUCUC CUGAUGAG GCCGUUAGGC CGAA AUCUUCUG 1971 1987 AUAGAGAU U CCCCUGGA197 UCCAGGGG CUGAUGAG GCCGUUAGGC CGAA AUCUCUAU 1972 1988 UAGAGAUU CCCCUGGAC 198 GUCCAGGG CUGAUGAG GCCGUUAGGC CGAA AAUCUCUA 1973 2004CCACACCU C CGUGGUUC 199 GAACCACG CUGAUGAG GCCGUUAGGC CGAA AGGUGUGG 19742011 UCCGUGGU U CACUUUGG 200 CCAAAGUG CUGAUGAG GCCGUUAGGC CGAA ACCACGGA1975 2012 CCGUGGUU C ACUUUGGU 201 ACCAAAGU CUGAUGAG GCCGUUAGGC CGAAAACCACGG 1976 2016 GGUUCACU U UGGUCACA 202 UGUGACCA CUGAUGAGGCCGUUAGGC CGAA AGUGAACC 1977 2017 GUUCACUU U GGUCACAA 203 UUGUGACCCUGAUGAG GCCGUUAGGC CGAA AAGUGAAC 1978 2021 ACUUUGGU C ACAAGUAG 204CUACUUGU CUGAUGAG GCCGUUAGGC CGAA ACCAAAGU 1979 2028 UCACAAGU A GGAGACAC205 GUGUCUCC CUGAUGAG GCCGUUAGGC CGAA ACUUGUGA 1980 2063 GAGCACCU CAGGACCCU 206 AGGGUCCU CUGAUGAG GCCGUUAGGC CGAA AGGUGCUC 1981 2072AGGACCCU C CCCACCCA 207 UGGGUGGG CUGAUGAG GCCGUUAGGC CGAA AGGGUCCU 19822091 AAAUGCCU C UGCCUUGA 208 UCAAGGCA CUGAUGAG GCCGUUAGGC CGAA AGGCAUUU1983 2097 CUCUGCCU U GAUGGAGA 209 UCUCCAUC CUGAUGAG GCCGUUAGGC CGAAAGGCAGAG 1984 2129 AGGUGGGU U CCAGGGAC 210 GUCCCUGG CUGAUGAGGCCGUUAGGC CGAA ACCCACCU 1985 2130 GGUGGGUU C CAGGGACU 211 AGUCCCUGCUGAUGAG GCCGUUAGGC CGAA AACCCACC 1986 2141 GGGACUGU A CCUGUAGG 212CCUACAGG CUGAUGAG GCCGUUAGGC CGAA ACAGUCCC 1987 2147 GUACCUGU A GGAAACAG213 CUGUUUCC CUGAUGAG GCCGUUAGGC CGAA ACAGGUAC 1988 2177 GAAGCACU CUGCUGGCG 214 CGCCAGCA CUGAUGAG GCCGUUAGGC CGAA AGUGCUUC 1989 2191GCGGGAAU A CUCUUGGU 215 ACCAAGAG CUGAUGAG GCCGUUAGGC CGAA AUUCCCGC 19902194 GGAAUACU C UUGGUCAC 216 GUGACCAA CUGAUGAG GCCGUUAGGC CGAA AGUAUUCC1991 2196 AAUACUCU U GGUCACCU 217 AGGUGACC CUGAUGAG GCCGUUAGGC CGAAAGAGUAUU 1992 2200 CUCUUGGU C ACCUCAAA 218 UUUGAGGU CUGAUGAGGCCGUUAGGC CGAA ACCAAGAG 1993 2205 GGUCACCU C AAAUUUAA 219 UUAAAUUUCUGAUGAG GCCGUUAGGC CGAA AGGUGACC 1994 2210 CCUCAAAU U UAAGUCGG 220CCGACUUA CUGAUGAG GCCGUUAGGC CGAA AUUUGAGG 1995 2211 CUCAAAUU U AAGUCGGG221 CCCGACUU CUGAUGAG GCCGUUAGGC CGAA AAUUUGAG 1996 2212 UCAAAUUU AAGUCUGGA 222 UCCCGACU CUGAUGAG GCCGUUAGGC CGAA AAAUUUGA 1997 2216AUUUAAGU C GGGAAAUU 223 AAUUUCCC CUGAUGAG GCCGUUAGGC CGAA ACUUAAAU 19982224 CGGGAAAU U CUGCUGCU 224 AGCAGCAG CUGAUGAG GCCGUUAGGC CGAA AUUUCCCG1999 2225 GGGAAAUU C UGCUGCUU 225 AAGCAGCA CUGAUGAG GCCGUUAGGC CGAAAAUUUCCC 2000 2233 CUGCUGCU U GAAACUUC 226 GAAGUUUC CUGAUGAGGCCGUUAGGC CGAA AGCAGCAG 2001 2240 UUGAAACU U CAGCCCUG 227 CAGGGCUGCUGAUGAG GCCGUUAGGC CGAA AGUUUCAA 2002 2241 UGAAACUU C AGCCCUGA 228UCAGGGCU CUGAUGAG GCCGUUAGGC CGAA AAGUUUCA 2003 2254 CUGAACCU U UGUCCACC229 GGUGGACA CUGAUGAG GCCGUUAGGC CGAA AGGUUCAG 2004 2255 UGAACCUU UGUCCACCA 230 UGGUGGAC CUGAUGAG GCCGUUAGGC CGAA AAGGUUCA 2005 2258ACCUUUGU C CACCAUUC 231 GAAUGGUG CUGAUGAG GCCGUUAGGC CGAA ACAAAGGU 20062265 UCCACCAU U CCUUUAAA 232 UUUAAAGG CUGAUGAG GCCGUUAGGC CGAA AUGGUGGA2007 2266 CCACCAUU C CUUUAAAU 233 AUUUAAAG CUGAUGAG GCCGUUAGGC CGAAAAUGGUGG 2008 2269 CCAUUCCU U UAAAUUCU 234 AGAAUUUA CUGAUGAGGCCGUUAGGC CGAA AGGAAUGG 2009 2270 CAUUCCUU U AAAUUCUC 235 GAGAAUUUCUGAUGAG GCCGUUAGGC CGAA AAGGAAUG 2010 2271 AUUCCUUU A AAUUCUCC 236GGAGAAUU CUGAUGAG GCCGUUAGGC CGAA AAAGGAAU 2011 2275 CUUUAAAU U CUCCAACC237 GGUUGGAG CUGAUGAG GCCGUUAGGC CGAA AUUUAAAG 2012 2276 UUUAAAUU CUCCAACCC 238 GGGUUGGA CUGAUGAG GCCGUUAGGC CGAA AAUUUAAA 2013 2278UAAAUUCU C CAACCCAA 239 UUGGGUUG CUGAUGAG GCCGUUAGGC CGAA AGAAUUUA 20142290 CCCAAAGU A UUCUUCUU 240 AAGAAGAA CUGAUGAG GCCGUUAGGC CGAA ACUUUGGG2015 2292 CAAAGUAU U CUUCUUUU 241 AAAAGAAG CUGAUGAG GCCGUUAGGC CGAAAUACUUUG 2016 2293 AAAGUAUU C UUCUUUUC 242 GAAAAGAA CUGAUGAGGCCGUUAGGC CGAA AAUACUUU 2017 2295 AGUAUUCU U CUUUUCUU 243 AAGAAAAGCUGAUGAG GCCGUUAGGC CGAA AGAAUACU 2018 2296 GUAUUCUU C UUUUCUUA 244UAAGAAAA CUGAUGAG GCCGUUAGGC CGAA AAGAAUAC 2019 2298 AUUCUUCU U UUCUUAGU245 ACUAAGAA CUGAUGAG GCCGUUAGGC CGAA AGAAGAAU 2020 2299 UUCUUCUU UUCUUAGUU 246 AACUAAGA CUGAUGAG GCCGUUAGGC CGAA AAGAAGAA 2021 2300UCUUCUUU U CUUAGUUU 247 AAACUAAG CUGAUGAG GCCGUUAGGC CGAA AAAGAAGA 20222301 CUUCUUUU C UUAGUUUC 248 GAAACUAA CUGAUGAG GCCGUUAGGC CGAA AAAAGAAG2023 2303 UCUUUUCU U AGUUUCAG 249 CUGAAACU CUGAUGAG GCCGUUAGGC CGAAAGAAAAGA 2024 2304 CUUUUCUU A GUUUCAGA 250 UCUGAAAC CUGAUGAGGCCGUUAGGC CGAA AAGAAAAG 2025 2307 UUCUUAGU U UCAGAAGU 251 ACUUCUGACUGAUGAG GCCGUUAGGC CGAA ACUAAGAA 2026 2308 UCUUAGUU U CAGAAGUA 252UACUUCUG CUGAUGAG GCCGUUAGGC CGAA AACUAAGA 2027 2309 CUUAGUUU C AGAAGUAC253 GUACUUCU CUGAUGAG GCCGUUAGGC CGAA AAACUAAG 2028 2316 UCAGAAGU ACUGGCAUC 254 GAUGCCAG CUGAUGAG GCCGUUAGGC CGAA ACUUCUGA 2029 2324ACUGGCAU C ACACGCAG 255 CUGCGUGU CUGAUGAG GCCGUUAGGC CGAA AUGCCAGU 20302335 ACGCAGGU U ACCUUGGC 256 GCCAAGGU CUGAUGAG GCCGUUAGGC CGAA ACCUGCGU2031 2336 CGCAGGUU A CCUUGGCG 257 CGCCAAGG CUGAUGAG GCCGUUAGGC CGAAAACCUGCG 2032 2340 GGUUACCU U GGCGUGUG 258 CACACGCC CUGAUGAGGCCGUUAGGC CGAA AGGUAACC 2033 2350 GCGUGUGU C CCUGUGGU 259 ACCACAGGCUGAUGAG GCCGUUAGGC CGAA ACACACGC 2034 2359 CCUGUGGU A CCCUGGCA 260UGCCAGGG CUGAUGAG GCCGUUAGGC CGAA ACCACAGG 2035 2384 ACCAAGCU U GUUUCCCU261 AGGGAAAC CUGAUGAG GCCGUUAGGC CGAA AGCUUGGU 2036 2387 AAGCUUGU UUCCCUGCU 262 AGCAGGGA CUGAUGAG GCCGUUAGGC CGAA ACAAGCUU 2037 2388AGCUUGUU U CCCUGCUG 263 CAGCAGGG CUGAUGAG GCCGUUAGGC CGAA AACAAGCU 20382389 GCUUGUUU C CCUGCUGG 264 CCAGCAGG CUGAUGAG GCCGUUAGGC CGAA AAACAAGC2039 2405 GCCAAAGU C AGUAGGAG 265 CUCCUACU CUGAUGAG GCCGUUAGGC CGAAACUUUGGC 2040 2409 AAGUCAGU A GGAGAGGA 266 UCCUCUCC CUGAUGAGGCCGUUAGGC CGAA ACUGACUU 2041 2426 UGCACAGU U UGCUAUUU 267 AAAUAGCACUGAUGAG GCCGUUAGGC CGAA ACUGUGCA 2042 2427 GCACAGUU U GCUAUUUG 268CAAAUAGC CUGAUGAG GCCGUUAGGC CGAA AACUGUGC 2043 2431 AGUUUGCU A UUUGCUUU269 AAAGCAAA CUGAUGAG GCCGUUAGGC CGAA AGCAAACU 2044 2433 UUUGCUAU UUGCUUUAG 270 CUAAAGCA CUGAUGAG GCCGUUAGGC CGAA AUAGCAAA 2045 2434UUGCUAUU U GCUUUAGA 271 UCUAAAGC CUGAUGAG GCCGUUAGGC CGAA AAUAGCAA 20462438 UAUUUGCU U UAGAGACA 272 UGUCUCUA CUGAUGAG GCCGUUAGGC CGAA AGCAAAUA2047 2439 AUUUGCUU U AGAGACAG 273 CUGUCUCU CUGAUGAG GCCGUUAGGC CGAAAAGCAAAU 2048 2440 UUUGCUUU A GAGACAGG 274 CCUGUCUC CUGAUGAGGCCGUUAGGC CGAA AAAGCAAA 2049 2455 GGGACUGU A UAAACAAG 275 CUUGUUUACUGAUGAG GCCGUUAGGC CGAA ACAGUCCC 2050 2457 GACUGUAU A AACAAGCC 276GGCUUGUU CUGAUGAG GCCGUUAGGC CGAA AUACAGUC 2051 2467 ACAAGCCU A ACAUUGGU277 ACCAAUGU CUGAUGAG GCCGUUAGGC CGAA AGGCUUGU 2052 2472 CCUAACAU UGGUGCAAA 278 UUUGCACC CUGAUGAG GCCGUUAGGC CGAA AUGUUAGG 2053 2484GCAAAGAU U GCCUCUUG 279 CAAGAGGC CUGAUGAG GCCGUUAGGC CGAA AUCUUUGC 20542489 GAUUGCCU C UUGAAUUA 280 UAAUUCAA CUGAUGAG GCCGUUAGGC CGAA AGGCAAUC2055 2491 UUGCCUCU U GAAUUAAA 281 UUUAAUUC CUGAUGAG GCCGUUAGGC CGAAAGAGGCAA 2056 2496 UCUUGAAU U AAAAAAAA 282 UUUUUUUU CUGAUGAGGCCGUUAGGC CGAA AUUCAAGA 2057 2497 CUUGAAUU A AAAAAAAA 283 UUUUUUUUCUGAUGAG GCCGUUAGGC CGAA AAUUCAAG 2058 2510 AAAAAACU A GAAAAAAA 284UUUUUUUC CUGAUGAG GCCGUUAGGC CGAA AGUUUUUU 2059

[0305] TABLE IV Human BACE Inozyme and Target Sequence Pos Substrate SeqID Inozyme Seq ID   10 CACGCGYC C GCAGCCCG 285 CGGGCUGC CUGAUGAGGCCGUUAGGC CGAA IACGCGUG 2060   13 GCGUCCGC A GCCCGCCC 286 GGGCGGGCCUGAUGAG GCCGUUAGGC CGAA ICGGACGC 2061   16 UCCGCAGC C CGCCCGGG 287CCCGGGCG CUGAUGAG GCCGUUAGGC CGAA ICUGCGGA 2062   17 CCGCAGCC C GCCCGGGA288 UCCCGGGC CUGAUGAG GCCGUUAGGC CGAA IGCUGCGG 2063   20 CAGCCCGC CCGGGAGCU 289 AGCUCCCG CUGAUGAG GCCGUUAGGC CGAA ICGGGCUG 2064   21AGCCCGCC C GGGAGCUG 290 CAGCUCCC CUGAUGAG GCCGUUAGGC CGAA IGCGGGCU 2065  28 CCGGGAGC U GCGAGCCG 291 CGGCUCGC CUGAUGAG GCCGUUAGGC CGAA ICUCCCGG2066   35 CUGCGAGC C GCGAGCUG 292 CAGCUCGC CUGAUGAG GCCGUUAGGC CGAAICUCGCAG 2067   42 CCGCGAGC U GGAUUAUG 293 CAUAAUCC CUGAUGAGGCCGUUAGGC CGAA ICUCGCGG 2068   56 AUGGUGGC C UGAGCAGC 294 GCUGCUCACUGAUGAG GCCGUUAGGC CGAA ICCACCAU 2069   57 UGGUGGCC U GAGCAGCC 295GGCUGCUC CUGAUGAG GCCGUUAGGC CGAA IGCCACCA 2070   62 GCCUGAGC A GCCAACGC296 GCGUUGGC CUGAUGAG GCCGUUAGGC CGAA ICUCAGGC 2071   65 UGAGCAGC CAACGCAGC 297 GCUGCGUU CUGAUGAG GCCGUUAGGC CGAA ICUGCUCA 2072   66GAGCAGCC A ACGCAGCC 298 GGCUGCGU CUGAUGAG GCCGUUAGGC CGAA IGCUGCUC 2073  71 GCCAACGC A GCCGCAGG 299 CCUGCGGC CUGAUGAG GCCGUUAGGC CGAA ICGUUGGC2074   74 AACGCAGC C GCAGGAGC 300 GCUCCUGC CUGAUGAG GCCGUUAGGC CGAAICUGCGUU 2075   77 GCAGCCGC A GGAGCCCG 301 CGGGCUCC CUGAUGAGGCCGUUAGGC CGAA ICGGCUGC 2076   83 GCAGGAGC C CGGAGCCC 302 GGGCUCCGCUGAUGAG GCCGUUAGGC CGAA ICUCCUGC 2077   84 CAGGAGCC C GGAGCCCU 303AGGGCUCC CUGAUGAG GCCGUUAGGC CGAA IGCUCCUG 2078   90 CCCGGAGC C CUUGCCCC304 GGGGCAAG CUGAUGAG GCCGUUAGGC CGAA ICUCCGGG 2079   91 CCGGAGCC CUUGCCCCU 305 AGGGGCAA CUGAUGAG GCCGUUAGGC CGAA IGCUCCGG 2080   92CGGAGCCC U UGCCCCUG 306 CAGGGGCA CUGAUGAG GCCGUUAGGC CGAA IGGCUCCG 2081  96 GCCCUUGC C CCUGCCCG 307 CGGGCAGG CUGAUGAG GCCGUUAGGC CGAA ICAAGGGC2082   97 CCCUUGCC C CUGCCCGC 308 GCGGGCAG CUGAUGAG GCCGUUAGGC CGAAIGCAAGGG 2083   98 CCUUGCCC C UGCCCGCG 309 CGCGGGCA CUGAUGAGGCCGUUAGGC CGAA IGGCAAGG 2084   99 CUUGCCCC U GCCCGCGC 310 GCGCGGGCCUGAUGAG GCCGUUAGGC CGAA IGGGCAAG 2085  102 GCCCCUGC C CGCGCCGC 311GCGGCGCG CUGAUGAG GCCGUUAGGC CGAA ICAGGGGC 2086  103 CCCCUGCC C GCGCCGCC312 GGCGGCGC CUGAUGAG GCCGUUAGGC CGAA IGCAGGGG 2087  108 GCCCGCGC CGCCGCCCG 313 CGGGCGGC CUGAUGAG GCCGUUAGGC CGAA ICGCGGGC 2088  111CGCGCCGC C GCCCGCCG 314 CGGCGGGC CUGAUGAG GCCGUUAGGC CGAA ICGGCGCG 2089 114 GCCGCCGC C CGCCGGGG 315 CCCCGGCG CUGAUGAG GCCGUUAGGC CGAA ICGGCGGC2090  115 CCGCCGCC C GCCGGGGG 316 CCCCCGGC CUGAUGAG GCCGUUAGGC CGAAIGCGGCGG 2091  118 CCGCCCGC C GGGGGGAC 317 GUCCCCCC CUGAUGAGGCCGUUAGGC CGAA ICGGGCGG 2092  127 GGGGGGAC C AGGGAAGC 318 GCUUCCCUCUGAUGAG GCCGUUAGGC CGAA IUCCCCCC 2093  128 GGGGGACC A GGGAAGCC 319GGCUUCCC CUGAUGAG GCCGUUAGGC CGAA IGUCCCCC 2094  136 AGGGAAGC C GCCACCGG320 CCGGUGGC CUGAUGAG GCCGUUAGGC CGAA ICUUCCCU 2095  139 GAAGCCGC CACCGGCCC 321 GGGCCGGU CUGAUGAG GCCGUUAGGC CGAA ICGGCUUC 2096  140AAGCCGCC A CCGGCCCG 322 CGGGCCGG CUGAUGAG GCCGUUAGGC CGAA IGCGGCUU 2097 142 GCCGCCAC C GGCCCGCC 323 GGCGGGCC CUGAUGAG GCCGUUAGGC CGAA IUGGCGGC2098  146 CCACCGGC C CGCCAUGC 324 GCAUGGCG CUGAUGAG GCCGUUAGGC CGAAICCGGUGG 2099  147 CACCGGCC C GCCAUGCC 325 GGCAUGGC CUGAUGAGGCCGUUAGGC CGAA IGCCGGUG 2100  150 CGGCCCGC C AUGCCCGC 326 GCGGGCAUCUGAUGAG GCCGUUAGGC CGAA ICGGGCCG 2101  151 GGCCCGCC A UGCCCGCC 327GGCGGGCA CUGAUGAG GCCGUUAGGC CGAA IGCGGGCC 2102  155 CGCCAUGC C CGCCCCUC328 GAGGGGCG CUGAUGAG GCCGUUAGGC CGAA ICAUGGCG 2103  156 GCCAUGCC CGCCCCUCC 329 GGAGGGGC CUGAUGAG GCCGUUAGGC CGAA IGCAUGGC 2104  159AUGCCCGC C CCUCCCAG 330 CUGGGAGG CUGAUGAG GCCGUUAGGC CGAA ICGGGCAU 2105 160 UGCCCGCC C CUCCCAGC 331 GCUGGGAG CUGAUGAG GCCGUUAGGC CGAA IGCGGGCA2106  161 GCCCGCCC C UCCCAGCC 332 GGCUGGGA CUGAUGAG GCCGUUAGGC CGAAIGGCGGGC 2107  162 CCCGCCCC U CCCAGCCC 333 GGGCUGGG CUGAUGAGGCCGUUAGGC CGAA IGGGCGGG 2108  164 CGCCCCUC C CAGCCCCG 334 CGGGGCUGCUGAUGAG GCCGUUAGGC CGAA IAGGGGCG 2109  165 GCCCCUCC C AGCCCCGC 335GCGGGGCU CUGAUGAG GCCGUUAGGC CGAA IGAGGGGC 2110  166 CCCCUCCC A GCCCCGCC336 GGCGGGGC CUGAUGAG GCCGUUAGGC CGAA IGGAGGGG 2111  169 CUCCCAGC CCCGCCGGG 337 CCCGGCGG CUGAUGAG GCCGUUAGGC CGAA ICUGGGAG 2112  170UCCCAGCC C CGCCGGGA 338 UCCCGGCG CUGAUGAG GCCGUUAGGC CGAA IGCUGGGA 2113 171 CCCAGCCC C GCCGGGAG 339 CUCCCGGC CUGAUGAG GCCGUUAGGC CGAA IGGCUGGG2114  174 AGCCCCGC C GGGAGCCC 340 GGGCUCCC CUGAUGAG GCCGUUAGGC CGAAICGGGGCU 2115  181 CCGGGAGC C CGCGCCCG 341 CGGGCGCG CUGAUGAGGCCGUUAGGC CGAA ICUCCCGG 2116  182 CGGGAGCC C GCGCCCGC 342 GCGGGCGCCUGAUGAG GCCGUUAGGC CGAA IGCUCCCG 2117  187 GCCCGCGC C CGCUGCCC 343GGGCAGCG CUGAUGAG GCCGUUAGGC CGAA ICGCGGGC 2118  188 CCCGCGCC C GCUGCCCA344 UGGGCAGC CUGAUGAG GCCGUUAGGC CGAA IGCGCGGG 2119  191 GCGCCCGC UGCCCAGGC 345 GCCUGGGC CUGAUGAG GCCGUUAGGC CGAA ICGGGCGC 2120  194CCCGCUGC C CAGGCUGG 346 CCAGCCUG CUGAUGAG GCCGUUAGGC CGAA ICAGCGGG 2121 195 CCGCUGCC C AGGCUGGC 347 GCCAGCCU CUGAUGAG GCCGUUAGGC CGAA IGCAGCGG2122  196 CGCUGCCC A GGCUGGCC 348 GGCCAGCC CUGAUGAG GCCGUUAGGC CGAAIGGCAGCG 2123  200 GCCCAGGC U GGCCGCCG 349 CGGCGGCC CUGAUGAGGCCGUUAGGC CGAA ICCUGGGC 2124  204 AGGCUGGC C GCCGCCGU 350 ACGGCGGCCUGAUGAG GCCGUUAGGC CGAA ICCAGCCU 2125  207 CUGGCCGC C GCCGUGCC 351GGCACGGC CUGAUGAG GCCGUUAGGC CGAA ICGGCCAG 2126  210 GCCGCCGC C GUGCCGAU352 AUCGGCAC CUGAUGAG GCCGUUAGGC CGAA ICGGCGGC 2127  215 CGCCGUGC CGAUGUAGC 353 GCUACAUC CUGAUGAG GCCGUUAGGC CGAA ICACGGCG 2128  228UAGCGGGC U CCGGAUCC 354 GGAUCCGG CUGAUGAG GCCGUUAGGC CGAA ICCCGCUA 2129 230 GCGGGCUC C GGAUCCCA 355 UGGGAUCC CUGAUGAG GCCGUUAGGC CGAA IAGCCCGC2130  236 UCCGGAUC C CAGCCUCU 356 AGAGGCUG CUGAUGAG GCCGUUAGGC CGAAIAUCCGGA 2131  237 CCGGAUCC C AGCCUCUC 357 GAGAGGCU CUGAUGAGGCCGUUAGGC CGAA IGAUCCGG 2132  238 CGGAUCCC A GCCUCUCC 358 GGAGAGGCCUGAUGAG GCCGUUAGGC CGAA IGGAUCCG 2133  241 AUCCCAGC C UCUCCCCU 359AGGGGAGA CUGAUGAG GCCGUUAGGC CGAA ICUGGGAU 2134  242 UCCCAGCC U CUCCCCUG360 CAGGGGAG CUGAUGAG GCCGUUAGGC CGAA IGCUGGGA 2135  244 CCAGCCUC UCCCCUGCU 361 AGCAGGGG CUGAUGAG GCCGUUAGGC CGAA IAGGCUGG 2136  246AGCCUCUC C CCUGCUCC 362 GGAGCAGG CUGAUGAG GCCGUUAGGC CGAA IAGAGGCU 2137 247 GCCUCUCC C CUGCUCCC 363 GGGAGCAG CUGAUGAG GCCGUUAGGC CGAA IGAGAGGC2138  248 CCUCUCCC C UGCUCCCG 364 CGGGAGCA CUGAUGAG GCCGUUAGGC CGAAIGGAGAGG 2139  249 CUCUCCCC U GCUCCCGU 365 ACGGGAGC CUGAUGAGGCCGUUAGGC CGAA IGGGAGAG 2140  252 UCCCCUGC U CCCGUGCU 366 AGCACGGGCUGAUGAG GCCGUUAGGC CGAA ICAGGGGA 2141  254 CCCUGCUC C CGUGCUCU 367AGAGCACG CUGAUGAG GCCGUUAGGC CGAA IAGCAGGG 2142  255 CCUGCUCC C GUGCUCUG368 CAGAGCAC CUGAUGAG GCCGUUAGGC CGAA IGAGCAGG 2143  260 UCCCGUGC UCUGCGGAU 369 AUCCGCAG CUGAUGAG GCCGUUAGGC CGAA ICACGGGA 2144  262CCGUGCUC U GCGGAUCU 370 AGAUCCGC CUGAUGAG GCCGUUAGGC CGAA IAGCACGG 2145 270 UGCGGAUC U CCCCUGAC 371 GUCAGGGG CUGAUGAG GCCGUUAGGC CGAA IAUCCGCA2146  272 CGGAUCUC C CCUGACCG 372 CGGUCAGG CUGAUGAG GCCGUUAGGC CGAAIAGAUCCG 2147  273 GGAUCUCC C CUGACCGC 373 GCGGUCAG CUGAUGAGGCCGUUAGGC CGAA IGAGAUCC 2148  274 GAUCUCCC C UGACCGCU 374 AGCGGUCACUGAUGAG GCCGUUAGGC CGAA IGGAGAUC 2149  275 AUCUCCCC U GACCGCUC 375GAGCGGUC CUGAUGAG GCCGUUAGGC CGAA IGGGAGAU 2150  279 CCCCUGAC C GCUCUCCA376 UGGAGAGC CUGAUGAG GCCGUUAGGC CGAA IUCAGGGG 2151  282 CUGACCGC UCUCCACAG 377 CUGUGGAG CUGAUGAG GCCGUUAGGC CGAA ICGGUCAG 2152  284GACCGCUC U CCACAGCC 378 GGCUGUGG CUGAUGAG GCCGUUAGGC CGAA IAGCGGUC 2153 286 CCGCUCUC C ACAGCCCG 379 CGGGCUGU CUGAUGAG GCCGUUAGGC CGAA IAGAGCGG2154  287 CGCUCUCC A CAGCCCGG 380 CCGGGCUG CUGAUGAG GCCGUUAGGC CGAAIGAGAGCG 2155  289 CUCUCCAC A GCCCGGAC 381 GUCCGGGC CUGAUGAGGCCGUUAGGC CGAA IUGGAGAG 2156  292 UCCACAGC C CGGACCCG 382 CGGGUCCGCUGAUGAG GCCGUUAGGC CGAA ICUGUGGA 2157  293 CCACAGCC C GGACCCGG 383CCGGGUCC CUGAUGAG GCCGUUAGGC CGAA IGCUGUGG 2158  298 GCCCGGAC C CGGGGGCU384 AGCCCCCG CUGAUGAG GCCGUUAGGC CGAA IUCCGGGC 2159  299 CCCGGACC CGGGGGCUG 385 CAGCCCCC CUGAUGAG GCCGUUAGGC CGAA IGUCCGGG 2160  306CCGGGGGC U GGCCCAGG 386 CCUGGGCC CUGAUGAG GCCGUUAGGC CGAA ICCCCCGG 2161 310 GGGCUGGC C CAGGGCCC 387 GGGCCCUG CUGAUGAG GCCGUUAGGC CGAA ICCAGCCC2162  311 GGCUGGCC C AGGGCCCU 388 AGGGCCCU CUGAUGAG GCCGUUAGGC CGAAIGCCAGCC 2163  312 GCUGGCCC A GGGCCCUG 389 CAGGGCCC CUGAUGAGGCCGUUAGGC CGAA IGGCCAGC 2164  317 CCCAGGGC C CUGCAGGC 390 GCCUGCAGCUGAUGAG GCCGUUAGGC CGAA ICCCUGGG 2165  318 CCAGGGCC C UGCAGGCC 391GGCCUGCA CUGAUGAG GCCGUUAGGC CGAA IGCCCUGG 2166  319 CAGGGCCC U GCAGGCCC392 GGGCCUGC CUGAUGAG GCCGUUAGGC CGAA IGGCCCUG 2167  322 GGCCCUGC AGGCCCUGG 393 CCAGGGCC CUGAUGAG GCCGUUAGGC CGAA ICAGGGCC 2168  326CUGCAGGC C CUGGCGUC 394 GACGCCAG CUGAUGAG GCCGUUAGGC CGAA ICCUGCAG 2169 327 UGCAGGCC C UGGCGUCC 395 GGACGCCA CUGAUGAG GCCGUUAGGC CGAA IGCCUGCA2170  328 GCAGGCCC U GGCGUCCU 396 AGGACGCC CUGAUGAG GCCGUUAGGC CGAAIGGCCUGC 2171  335 CUGGCGUC C UGAUGCCC 397 GGGCAUCA CUGAUGAGGCCGUUAGGC CGAA IACGCCAG 2172  336 UGGCGUCC U GAUGCCCC 398 GGGGCAUCCUGAUGAG GCCGUUAGGC CGAA IGACGCCA 2173  342 CCUGAUGC C CCCAAGCU 399AGCUUGGG CUGAUGAG GCCGUUAGGC CGAA ICAUCAGG 2174  343 CUGAUGCC C CCAAGCUC400 GAGCUUGG CUGAUGAG GCCGUUAGGC CGAA IGCAUCAG 2175  344 UGAUGCCC CCAAGCUCC 401 GGAGCUUG CUGAUGAG GCCGUUAGGC CGAA IGGCAUCA 2176  345GAUGCCCC C AAGCUCCC 402 GGGAGCUU CUGAUGAG GCCGUUAGGC CGAA IGGGCAUC 2177 346 AUGCCCCC A AGCUCCCU 403 AGGGAGCU CUGAUGAG GCCGUUAGGC CGAA IGGGGCAU2178  350 CCCCAAGC U CCCUCUCC 404 GGAGAGGG CUGAUGAG GCCGUUAGGC CGAAICUUGGGG 2179  352 CCAAGCUC C CUCUCCUG 405 CAGGAGAG CUGAUGAGGCCGUUAGGC CGAA IAGCUUGG 2180  353 CAAGCUCC C UCUCCUGA 406 UCAGGAGACUGAUGAG GCCGUUAGGC CGAA IGAGCUUG 2181  354 AAGCUCCC U CUCCUGAG 407CUCAGGAG CUGAUGAG GCCGUUAGGC CGAA IGGAGCUU 2182  356 GCUCCCUC U CCUGAGAA408 UUCUCAGG CUGAUGAG GCCGUUAGGC CGAA IAGGGAGC 2183  358 UCCCUCUC CUGAGAAGC 409 GCUUCUCA CUGAUGAG GCCGUUAGGC CGAA IAGAGGA 2184  359CCCUCUCC U GAGAAGCC 410 GGCUUCUC CUGAUGAG GCCGUUAGGC CGAA IGAGAGGG 2185 367 UGAGAAGC C ACCAGCAC 411 GUGCUGGU CUGAUGAG GCCGUUAGGC CGAA ICUUCUCA2186  368 GAGAAGCC A CCAGCACC 412 GGUGCUGG CUGAUGAG GCCGUUAGGC CGAAIGCUUCUC 2187  370 GAAGCCAC C AGCACCAC 413 GUGGUGCU CUGAUGAGGCCGUUAGGC CGAA IUGGCUUC 2188  371 AAGCCACC A GCACCACC 414 GGUGGUGCCUGAUGAG GCCGUUAGGC CGAA IGUGGCUU 2189  374 CCACCAGC A CCACCCAG 415CUGGGUGG CUGAUGAG GCCGUUAGGC CGAA ICUGGUGG 2190  376 ACCAGCAC C ACCCAGAC416 GUCUGGGU CUGAUGAG GCCGUUAGGC CGAA IUGCUGGU 2191  377 CCAGCACC ACCCAGACU 417 AGUCUGGG CUGAUGAG GCCGUUAGGC CGAA IGUGCUGG 2192  379AGCACCAC C CAGACUUG 418 CAAGUCUG CUGAUGAG GCCGUUAGGC CGAA IUGGUGCU 2193 380 GCACCACC C AGACUUGG 419 CCAAGUCU CUGAUGAG GCCGUUAGGC CGAA IGUGGUGC2194  381 CACCACCC A GACUUGGG 420 CCCAAGUC CUGAUGAG GCCGUUAGGC CGAAIGGUGGUG 2195  385 ACCCAGAC U UGGGGGCA 421 UGCCCCCA CUGAUGAGGCCGUUAGGC CGAA IUCUGGGU 2196  393 UUGGGGGC A GGCGCCAG 422 CUGGCGCCCUGAUGAG GCCGUUAGGC CGAA ICCCCCAA 2197  399 GCAGGCGC C AGGGACGG 423CCGUCCCU CUGAUGAG GCCGUUAGGC CGAA ICGCCUGC 2198  400 CAGGCGCC A GGGACGGA424 UCCGUCCC CUGAUGAG GCCGUUAGGC CGAA IGCGCCUG 2199  416 ACGUGGGC CAGUGCGAG 425 CUCGCACU CUGAUGAG GCCGUUAGGC CGAA ICCCACGU 2200  417CGUGGGCC A GUGCGAGC 426 GCUCGCAC CUGAUGAG GCCGUUAGGC CGAA IGCCCACG 2201 426 GUGCGAGC C CAGAGGGC 427 GCCCUCUG CUGAUGAG GCCGUUAGGC CGAA ICUCGCAC2202  427 UGCGAGCC C AGAGGGCC 428 GGCCCUCU CUGAUGAG GCCGUUAGGC CGAAIGCUCGCA 2203  428 GCGAGCCC A GAGGGCCC 429 GGGCCCUC CUGAUGAGGCCGUUAGGC CGAA IGGCUCGC 2204  435 CAGAGGGC C CGAAGGCC 430 GGCCUUCGCUGAUGAG GCCGUUAGGC CGAA ICCCUCUG 2205  436 AGAGGGCC C GAAGGCCG 431CGGCCUUC CUGAUGAG GCCGUUAGGC CGAA IGCCCUCU 2206  443 CCGAAGGC C GGGGCCCA432 UGGGCCCC CUGAUGAG GCCGUUAGGC CGAA ICCUUCGG 2207  449 GCCGGGGC CCACCAUGG 433 CCAUGGUG CUGAUGAG GCCGUUAGGC CGAA ICCCCGGC 2208  450CCGGGGCC C ACCAUGGC 434 GCCAUGGU CUGAUGAG GCCGUUAGGC CGAA IGCCCCGG 2209 451 CGGGGCCC A CCAUGGCC 435 GGCCAUGG CUGAUGAG GCCGUUAGGC CGAA IGGCCCCG2210  453 GGGCCCAC C AUGGCCCA 436 UGGGCCAU CUGAUGAG GCCGUUAGGC CGAAIUGGGCCC 2211  454 GGCCCACC A UGGCCCAA 437 UUGGGCCA CUGAUGAGGCCGUUAGGC CGAA IGUGGGCC 2212  459 ACCAUGGC C CAAGCCCU 438 AGGGCUUGCUGAUGAG GCCGUUAGGC CGAA ICCAUGGU 2213  460 CCAUGGCC C AAGCCCUG 439CAGGGCUU CUGAUGAG GCCGUUAGGC CGAA IGCCAUGG 2214  461 CAUGGCCC A AGCCCUGC440 GCAGGGCU CUGAUGAG GCCGUUAGGC CGAA IGGCCAUG 2215  465 GCCCAAGC CCUGCCCUG 441 CAGGGCAG CUGAUGAG GCCGUUAGGC CGAA ICUUGGGC 2216  466CCCAAGCC C UGCCCUGG 442 CCAGGGCA CUGAUGAG GCCGUUAGGC CGAA IGCUUGGG 2217 467 CCAAGCCC U GCCCUGGC 443 GCCAGGGC CUGAUGAG GCCGUUAGGC CGAA IGGCUUGG2218  470 AGCCCUGC C CUGGCUCC 444 GGAGCCAG CUGAUGAG GCCGUUAGGC CGAAICAGGGCU 2219  471 GCCCUGCC C UGGCUCCU 445 AGGAGCCA CUGAUGAGGCCGUUAGGC CGAA IGCAGGGC 2220  472 CCCUGCCC U GGCUCCUG 446 CAGGAGCCCUGAUGAG GCCGUUAGGC CGAA IGGCAGGG 2221  476 GCCCUGGC U CCUGCUGU 447ACAGCAGG CUGAUGAG GCCGUUAGGC CGAA ICCAGGGC 2222  478 CCUGGCUC C UGCUGUGG448 CCACAGCA CUGAUGAG GCCGUUAGGC CGAA IAGCCAGG 2223  479 CUGGCUCC UGCUGUGGA 449 UCCACAGC CUGAUGAG GCCGUUAGGC CGAA IGAGCCAG 2224  482GCUCCUGC U GUGGAUGG 450 CCAUCCAC CUGAUGAG GCCGUUAGGC CGAA ICAGGAGC 2225 503 GGGAGUGC U GCCUGCCC 451 GGGCAGGC CUGAUGAG GCCGUUAGGC CGAA ICACUCCC2226  506 AGUGCUGC C UGCCCACG 452 CGUGGGCA CUGAUGAG GCCGUUAGGC CGAAICAGCACU 2227  507 GUGCUGCC U GCCCACGG 453 CCGUGGGC CUGAUGAGGCCGUUAGGC CGAA IGCAGCAC 2228  510 CUGCCUGC C CACGGCAC 454 GUGCCGUGCUGAUGAG GCCGUUAGGC CGAA ICAGGCAG 2229  511 UGCCUGCC C ACGGCACC 455GGUGCCGU CUGAUGAG GCCGUUAGGC CGAA IGCAGGCA 2230  512 GCCUGCCC A CGGCACCC456 GGGUGCCG CUGAUGAG GCCGUUAGGC CGAA IGGCAGGC 2231  517 CCCACGGC ACCCAGCAC 457 GUGCUGGG CUGAUGAG GCCGUUAGGC CGAA ICCGUGGG 2232  519CACGGCAC C CAGCACGG 458 CCGUGCUG CUCAUGAG GCCGUUAGGC CGAA IUGCCGUG 2233 520 ACGGCACC C AGCACGGC 459 GCCGUGCU CUGAUGAG GCCGUUAGGC CGAA IGUGCCGU2234  521 CGGCACCC A GCACGGCA 460 UGCCGUGC CUGAUGAG GCCGUUAGGC CGAAIGGUGCCG 2235  524 CACCCAGC A CGGCAUCC 461 GGAUGCCG CUGAUGAGGCCGUUAGGC CGAA ICUGGGUG 2236  529 AGCACGGC A UCCGGCUG 462 CAGCCGGACUGAUGAG GCCGUUAGGC CGAA ICCGUGCU 2237  532 ACGGCAUC C GGCUGCCC 463GGGCAGCC CUGAUGAG GCCGUUAGGC CGAA IAUGCCGU 2238  536 CAUCCGGC U GCCCCUGC464 GCAGGGGC CUGAUGAG GCCGUUAGGC CGAA ICCGGAUG 2239  539 CCGGCUGC CCCUGCGCA 465 UGCGCAGG CUGAUGAG GCCGUUAGGC CGAA ICAGCCGG 2240  540CGGCUGCC C CUGCGCAG 466 CUGCGCAG CUGAUGAG GCCGUUAGGC CGAA IGCAGCCG 2241 541 GGCUGCCC C UGCGCAGC 467 GCUGCGCA CUGAUGAG GCCGUUAGGC CGAA IGGCAGCC2242  542 GCUGCCCC U GCGCAGCG 468 CGCUGCGC CUGAUGAG GCCGUUAGGC CGAAIGGGCAGC 2243  547 CCCUGCGC A GCGGCCUG 469 CAGGCCGC CUGAUGAGGCCGUUAGGC CGAA ICGCAGGG 2244  553 GCAGCGGC C UGGGGGGC 470 GCCCCCCACUGAUGAG GCCGUUAGGC CGAA ICCGCUGC 2245  554 CAGCGGCC U GGGGGGCG 471CGCCCCCC CUGAUGAG GCCGUUAGGC CGAA IGCCGCUG 2246  564 GGGGGCGC C CCCCUGGG472 CCCAGGGG CUGAUGAG GCCGUUAGGC CGAA ICGCCCCC 2247  565 GGGGCGCC CCCCUGGGG 473 CCCCAGGG CUGAUGAG GCCGUUAGGC CGAA IGCGCCCC 2248  566GGGCGCCC C CCUGGGGC 474 GCCCCAGG CUGAUGAG GCCGUUAGGC CGAA IGGCGCCC 2249 567 GGCGCCCC C CUGGGGCU 475 AGCCCCAG CUGAUGAG GCCGUUAGGC CGAA IGGGCGCC2250  568 GCGCCCCC C UGGGGCUG 476 CAGCCCCA CUGAUGAG GCCGUUAGGC CGAAIGGGGCGC 2251  569 CGCCCCCC U GGGGCUGC 477 GCAGCCCC CUGAUGAGGCCGUUAGGC CGAA IGGGGGCG 2252  575 CCUGGGGC U GCGGCUGC 478 GCAGCCGCCUGAUGAG GCCGUUAGGC CGAA ICCCCAGG 2253  581 GCUGCGGC U GCCCCGGG 479CCCGGGGC CUGAUGAG GCCGUUAGGC CGAA ICCGCAGC 2254  584 GCGGCUGC C CCGGGAGA480 UCUCCCGG CUGAUGAG GCCGUUAGGC CGAA ICAGCCGC 2255  585 CGGCUGCC CCGGGAGAC 481 GUCUCCCG CUGAUGAG GCCGUUAGGC CGAA IGCAGCCG 2256  586GGCUGCCC C GGGAGACC 482 GGUCUCCC CUGAUGAG GCCGUUAGGC CGAA IGGCAGCC 2257 594 CGGGAGAC C GACGAAGA 483 UCUUCGUC CUGAUGAG GCCGUUAGGC CGAA IUCUCCCG2258  605 CGAAGAGC C CGAGGAGC 484 GCUCCUCG CUGAUGAG GCCGUUAGGC CGAAICUCUUCG 2259  606 GAAGAGCC C GAGGAGCC 485 GGCUCCUC CUGAUGAGGCCGUUAGGC CGAA IGCUCUUC 2260  614 CGAGGAGC C CGGCCGGA 486 UCCGGCCGCUGAUGAG GCCGUUAGGC CGAA ICUCCUCG 2261  615 GAGGAGCC C GGCCGGAG 487CUCCGGCC CUGAUGAG GCCGUUAGGC CGAA IGCUCCUC 2262  619 AGCCCGGC C GGAGGGGC488 GCCCCUCC CUGAUGAG GCCGUUAGGC CGAA ICCGGGCU 2263  628 GGAGGGGC AGCUUUGUG 489 CACAAAGC CUGAUGAG GCCGUUAGGC CGAA ICCCCUCC 2264  631GGGGCAGC U UUGUGGAG 490 CUCCACAA CUGAUGAG GCCGUUAGGC CGAA ICUGCCCC 2265 649 UGGUGGAC A ACCUGAGG 491 CCUCAGGU CUGAUGAG GCCGUUAGGC CGAA IUCCACCA2266  652 UGGACAAC C UGAGGGGC 492 GCCCCUCA CUGAUGAG GCCGUUAGGC CGAAIUUGUCCA 2267  653 GGACAACC U GAGGGGCA 493 UGCCCCUC CUGAUGAGGCCGUUAGGC CGAA IGUUGUCC 2268  661 UGAGGGGC A AGUCGGGG 494 CCCCGACUCUGAUGAG GCCGUUAGGC CGAA ICCCCUCA 2269  671 GUCGGGGC A GGGCUACU 495AGUAGCCC CUGAUGAG GCCGUUAGGC CGAA ICCCCGAC 2270  676 GGCAGGGC U ACUACGUG496 CACGUAGU CUGAUGAG GCCGUUAGGC CGAA ICCCUGCC 2271  679 AGGGCUAC UACGUGGAG 497 CUCCACGU CUGAUGAG GCCGUUAGGC CGAA IUAGCCCU 2272  693GAGAUGAC C GUGGGCAG 498 CUGCCCAC CUGAUGAG GCCGUUAGGC CGAA IUCAUCUC 2273 700 CCGUGGGC A GCCCCCCG 499 CGGGGGGC CUGAUGAG GCCGUUAGGC CGAA ICCCACGG2274  703 UGGGCAGC C CCCCGCAG 500 CUGCGGGG CUGAUGAG GCCGUUAGGC CGAAICUGCCCA 2275  704 GGGCAGCC C CCCGCAGA 501 UCUGCGGG CUGAUGAGGCCGUUAGGC CGAA IGCUGCCC 2276  705 GGCAGCCC C CCGCAGAC 502 GUCUGCGGCUGAUGAG GCCGUUAGGC CGAA IGGCUGCC 2277  706 GCAGCCCC C CGCAGACG 503CGUCUGCG CUGAUGAG GCCGUUAGGC CGAA IGGGCUGC 2278  707 CAGCCCCC C GCAGACGC504 GCGUCUGC CUGAUGAG GCCGUUAGGC CGAA IGGGGCUG 2279  710 CCCCCCGC AGACGCUCA 505 UGAGCGUC CUGAUGAG GCCGUUAGGC CGAA ICGGGGGG 2280  716GCAGACGC U CAACAUCC 506 GGAUGUUG CUGAUGAG GCCGUUAGGC CGAA ICGUCUGC 2281 718 AGACGCUC A ACAUCCUG 507 CAGGAUGU CUGAUGAG GCCGUUAGGC CGAA IAGCGUCU2282  721 CGCUCAAC A UCCUGGUG 508 CACCAGGA CUGAUGAG GCCGUUAGGC CGAAIUUGAGCG 2283  724 UCAACAUC C UGGUGGAU 509 AUCCACCA CUGAUGAGGCCGUUAGGC CGAA IAUGUUGA 2284  725 CAACAUCC U GGUGGAUA 510 UAUCCACCCUGAUGAG GCCGUUAGGC CGAA IGAUGUUG 2285  735 GUGGAUAC A GGCAGCAG 511CUGCUGCC CUGAUGAG GCCGUUAGGC CGAA IUAUCCAC 2286  739 AUACAGGC A GCAGUAAC512 GUUACUGC CUGAUGAG GCCGUUAGGC CGAA ICCUGUAU 2287  742 CAGGCAGC AGUAACUUU 513 AAAGUUAC CUGAUGAG GCCGUUAGGC CGAA ICUGCCUG 2288  748GCAGUAAC U UUGCAGUG 514 CACUGCAA CUGAUGAG GCCGUUAGGC CGAA IUUACUGC 2289 753 AACUUUGC A GUGGGUGC 515 GCACCCAC CUGAUGAG GCCGUUAGGC CGAA ICAAAGUU2290  762 GUGGGUGC U GCCCCCCA 516 UGGGGGGC CUGAUGAG GCCGUUAGGC CGAAICACCCAC 2291  765 GGUGCUGC C CCCCACCC 517 GGGUGGGG CUGAUGAGGCCGUUAGGC CGAA ICAGCACC 2292  766 GUGCUGCC C CCCACCCC 518 GGGGUGGGCUGAUGAG GCCGUUAGGC CGAA IGCAGCAC 2293  767 UGCUGCCC C CCACCCCU 519AGGGGUGG CUGAUGAG GCCGUUAGGC CGAA IGGCAGCA 2294  768 GCUGCCCC C CACCCCUU520 AAGGGGUG CUGAUGAG GCCGUUAGGC CGAA IGGGCAGC 2295  769 CUGCCCCC CACCCCUUC 521 GAAGGGGU CUGAUGAG GCCGUUAGGC CGAA IGGGGCAG 2296  770UGCCCCCC A CCCCUUCC 522 GGAAGGGG CUGAUGAG GCCGUUAGGC CGAA IGGGGGCA 2297 772 CCCCCCAC C CCUUCCUG 523 CAGGAAGG CUGAUGAG GCCGUUAGGC CGAA IUGGGGGG2298  773 CCCCCACC C CUUCCUGC 524 GCAGGAAG CUGAUGAG GCCGUUAGGC CGAAIGUGGGGG 2299  774 CCCCACCC C UUCCUGCA 525 UGCAGGAA CUGAUGAGGCCGUUAGGC CGAA IGGUGGGG 2300  775 CCCACCCC U UCCUGCAU 526 AUGCAGGACUGAUGAG GCCGUUAGGC CGAA IGGGUGGG 2301  778 ACCCCUUC C UGCAUCGC 527GCGAUGCA CUGAUGAG GCCGUUAGGC CGAA IAAGGGGU 2302  779 CCCCUUCC U GCAUCGCU528 AGCGAUGC CUGAUGAG GCCGUUAGGC CGAA IGAAGGGG 2303  782 CUUCCUGC AUCGCUACU 529 AGUAGCGA CUGAUGAG GCCGUUAGGC CGAA ICAGGAAG 2304  787UGCAUCGC U ACUACCAG 530 CUGGUAGU CUGAUGAG GCCGUUAGGC CGAA ICGAUGCA 2305 790 AUCGCUAC U ACCAGAGG 531 CCUCUGGU CUGAUGAG GCCGUUAGGC CGAA IUAGCGAU2306  793 GCUACUAC C AGAGGCAG 532 CUGCCUCU CUGAUGAG GCCGUUAGGC CGAAIUAGUAGC 2307  794 CUACUACC A GAGGCAGC 533 GCUGCCUC CUGAUGAGGCCGUUAGGC CGAA IGUAGUAG 2308  800 CCAGAGGC A GCUGUCCA 534 UGGACAGCCUGAUGAG GCCGUUAGGC CGAA ICCUCUGG 2309  803 GAGGCAGC U GUCCAGCA 535UGCUGGAC CUGAUGAG GCCGUUAGGC CGAA ICUGCCUC 2310  807 CAGCUGUC C AGCACAUA536 UAUGUGCU CUGAUGAG GCCGUUAGGC CGAA IACAGCUG 2311  808 AGCUGUCC AGCACAGAC 537 GUAUGUGC CUGAUGAG GCCGUUAGGC CGAA IGACAGCU 2312  811UGUCCAGC A CAUACCGG 538 CCGGUAUG CUGAUGAG GCCGUUAGGC CGAA ICUGGACA 2313 813 UCCAGCAC A UACCGGGA 539 UCCCGGUA CUGAUGAG GCCGUUAGGC CGAA IUGCUGGA2314  817 GCACAUAC C GGGACCUC 540 GAGGUCCC CUGAUGAG GCCGUUAGGC CGAAIUAUGUGC 2315  823 ACCGGGAC C UCCGGAAG 541 CUUCCGGA CUGAUGAGGCCGUUAGGC CGAA IUCCCGGU 2316  824 CCGGGACC U CCGGAAGG 542 CCUUCCGGCUGAUGAG GCCGUUAGGC CGAA IGUCCCGG 2317  826 GGGACCUC C GGAAGGGU 543ACCCUUCC CUGAUGAG GCCGUUAGGC CGAA IAGGUCCC 2318  845 GUAUGUGC C CUACACCC544 GGGUGUAG CUGAUGAG GCCGUUAGGC CGAA ICACAUAC 2319  846 UAUGUGCC CUACACCCA 545 UGGGUGUA CUGAUGAG GCCGUUAGGC CGAA IGCACAUA 2320  847AUGUGCCC U ACACCCAG 546 CUGGGUGU CUGAUGAG GCCGUUAGGC CGAA IGGCACAU 2321 850 UGCCCUAC A CCCAGGGC 547 GCCCUGGG CUGAUGAG GCCGUUAGGC CGAA IUAGGGCA2322  852 CCCUACAC C CAGGGCAA 548 UUGCCCUG CUGAUGAG GCCGUUAGGC CGAAIUGUAGGG 2323  853 CCUACACC C AGGGCAAG 549 CUUGCCCU CUGAUGAGGCCGUUAGGC CGAA IGUGUAGG 2324  854 CUACACCC A GGGCAAGU 550 ACUUGCCCCUGAUGAG GCCGUUAGGC CGAA IGGUGUAG 2325  859 CCCAGGGC A AGUGGGAA 551UUCCCACU CUGAUGAG GCCGUUAGGC CGAA ICCCUGGG 2326  875 AGGGGAGC U GGGCACCG552 CGGUGCCC CUGAUGAG GCCGUUAGGC CGAA ICUCCCCU 2327  880 AGCUGGGC ACCGACCUG 553 CAGGUCGG CUGAUGAG GCCGUUAGGC CGAA ICCCAGCU 2328  882CUGGGCAC C GACCUGGU 554 ACCAGGUC CUGAUGAG GCCGUUAGGC GCAA IUGCCCAG 2329 886 GCACCGAC C UGGUAAGC 555 GCUUACCA CUGAUGAG GCCGUUAGGC CGAA IUCGGUGC2330  887 CACCGACC U GGUAAGCA 556 UGCUUACC CUGAUGAG GCCGUUAGGC CGAAIGUCGGUG 2331  895 UGGUAAGC A UCCCCCAU 557 AUGGGGGA CUGAUGAGGCCGUUAGGC CGAA ICUUACCA 2332  898 UAAGCAUC C CCCAUGGC 558 GCCAUGGGCUGAUGAG GCCGUUAGGC CGAA IAUGCUUA 2333  899 AAGCAUCC C CCAUGGCC 559GGCCAUGG CUGAUGAG GCCGUUAGGC CGAA IGAUGCUU 2334  900 AGCAUCCC C CAUGGCCC560 GGGCCAUG CUGAUGAG GCCGUUAGGC CGAA IGGAUGCU 2335  901 GCAUCCCC CAUGGCCCC 561 GGGGCCAU CUGAUGAG GCCGUUAGGC CGAA IGGGAUGC 2336  902CAUCCCCC A UGGCCCCA 562 UGGGGCCA CUGAUGAG GCCGUUAGGC CGAA IGGGGAUG 2337 907 CCCAUGGC C CCAACGUC 563 GACGUUGG CUGAUGAG GCCGUUAGGC CGAA ICCAUGGG2338  908 CCAUGGCC C CAACGUCA 564 UGACGUUG CUGAUGAG GCCGUUAGGC CGAAIGCCAUGG 2339  909 CAUGGCCC C AACGUCAC 565 GUGACGUU CUGAUGAGGCCGUUAGGC CGAA IGGCCAUG 2340  910 AUGGCCCC A ACGUCACU 566 AGUGACGUCUGAUGAG GCCGUUAGGC CGAA IGGGCCAU 2341  916 CCAACGUC A CUGUGCGU 567ACGCACAG CUGAUGAG GCCGUUAGGC CGAA IACGUUGG 2342  918 AACGUCAC U GUGCGUGC568 GCACGCAC CUGAUGAG GCCGUUAGGC CGAA IUGACGUU 2343  927 GUGCGUGC CAACAUUGC 569 GCAAUGUU CUGAUGAG GCCGUUAGGC CGAA ICACGCAC 2344  928UGCGUGCC A ACAUUGCU 570 AGCAAUGU CUGAUGAG GCCGUUAGGC CGAA IGCACGCA 2345 931 GUGCCAAC A UUGCUGCC 571 GGCAGCAA CUGAUGAG GCCGUUAGGC CGAA IUUGGCAC2346  936 AACAUUGC U GCCAUCAC 572 GUGAUGGC CUGAUGAG GCCGUUAGGC CGAAICAAUGUU 2347  939 AUUGCUGC C AUCACUGA 573 UCAGUGAU CUGAUGAGGCCGUUAGGC CGAA ICAGCAAU 2348  940 UUGCUGCC A UCACUGAA 574 UUCAGUGACUGAUGAG GCCGUUAGGC CGAA IGCAGCAA 2349  943 CUGCCAUC A CUGAAUCA 575UGAUUCAG CUGAUGAG GCCGUUAGGC CGAA IAUGGCAG 2350  945 GCCAUCAC U GAAUCAGA576 UCUGAUUC CUGAUGAG GCCGUUAGGC CGAA IUGAUGGC 2351  951 ACUGAAUC AGACAAGUU 577 AACUUGUC CUGAUGAG GCCGUUAGGC CGAA IAUUCAGU 2352  955AAUCAGAC A AGUUCUUC 578 GAAGAACU CUGAUGAG GCCGUUAGGC CGAA IUCUGAUU 2353 961 ACAAGUUC U UCAUCAAC 579 GUUGAUGA CUGAUGAG GCCGUUAGGC CGAA IAACUUGU2354  964 AGUUCUUC A UCAACGGC 580 GCCGUUGA CUGAUGAG GCCGUUAGGC CGAAIAAGAACU 2355  967 UCUUCAUC A ACGGCUCC 581 GGAGCCGU CUGAUGAGGCCGUUAGGC CGAA IAUGAAGA 2356  973 UCAACGGC U CCAACUGG 582 CCAGUUGGCUGAUGAG GCCGUUAGGC CGAA ICCGUUGA 2357  975 AACGGCUC C AACUGGGA 583UCCCAGUU CUGAUGAG GCCGUUAGGC CGAA IAGCCGUU 2358  976 ACGGCUCC A ACUGGGAA584 UUCCCAGU CUGAUGAG GCCGUUAGGC CGAA IGAGCCGU 2359  979 GCUCCAAC UGGGAAGGC 585 GCCUUCCC CUGAUGAG GCCGUUAGGC CGAA IUUGGAGC 2360  988GGGAAGGC A UCCUGGGG 586 CCCCAGGA CUGAUGAG GCCGUUAGGC CGAA ICCUUCCC 2361 991 AAGGCAUC C UGGGGCUG 587 CAGCCCCA CUGAUGAG GCCGUUAGGC CGAA IAUGCCUU2362  992 AGGCAUCC U GGGGCUGG 588 CCAGCCCC CUGAUGAG GCCGUUAGGC CGAAIGAUGCCU 2363  998 CCUGGGGC U GGCCUAUG 589 CAUAGGCC CUGAUGAGGCCGUUAGGC CGAA ICCCCAGG 2364 1002 GGGCUGGC C UAUGCUGA 590 UCAGCAUACUGAUGAG GCCGUUAGGC CGAA ICCAGCCC 2365 1003 GGCUGGCC U AUGCUGAG 591CUCAGCAU CUGAUGAG GCCGUUAGGC CGAA IGCCAGCC 2366 1008 GCCUAUGC U GAGAUUGC592 GCAAUCUC CUGAUGAG GCCGUUAGGC CGAA ICAUAGGC 2367 1017 GAGAUUGC CAGGCCUGA 593 UCAGGCCU CUGAUGAG GCCGUUAGGC CGAA ICAAUCUC 2368 1018AGAUUGCC A GGCCUGAC 594 GUCAGGCC CUGAUGAG GCCGUUAGGC CGAA IGCAAUCU 23691022 UGCCAGGC C UGACGACU 595 AGUCGUCA CUGAUGAG GCCGUUAGGC CGAA ICCUGGCA2370 1023 GCCAGGCC U GACGACUC 596 GAGUCGUC CUGAUGAG GCCGUUAGGC CGAAIGCCUGGC 2371 1030 CUGACGAC U CCCUGGAG 597 CUCCAGGG CUGAUGAGGCCGUUAGGC CGAA IUCGUCAG 2372 1032 GACGACUC C CUGGAGCC 598 GGCUCCAGCUGAUGAG GCCGUUAGGC CGAA IAGUCGUC 2373 1033 ACGACUCC C UGGAGCCU 599AGGCUCCA CUGAUGAG GCCGUUAGGC CGAA IGAGUCGU 2374 1034 CGACUCCC U GGAGCCUU600 AAGGCUCC CUGAUGAG GCCGUUAGGC CGAA IGGAGUCG 2375 1040 CCUGGAGC CUUUCUUUG 601 CAAAGAAA CUGAUGAG GCCGUUAGGC CGAA ICUCCAGG 2376 1041CUGGAGCC U UUCUUUGA 602 UCAAAGAA CUGAUGAG GCCGUUAGGC CGAA IGCUCCAG 23771045 AGCCUUUC U UUGACUCU 603 AGAGUCAA CUGAUGAG GCCGUUAGGC CGAA IAAAGGCU2378 1051 UCUUUGAC U CUCUGGUA 604 UACCAGAG CUGAUGAG GCCGUUAGGC CGAAIUCAAAGA 2379 1053 UUUGACUC U CUGGUAAA 605 UUUACCAG CUGAUGAGGCCGUUAGGC CGAA IAGUCAAA 2380 1055 UGACUCUC U GGUAAAGC 606 GCUUUACCCUGAUGAG GCCGUUAGGC CGAA UAGAGUCA 2381 1064 GGUAAAGC A GACCCACG 607CGUGGGUC CUGAUGAG GCCGUUAGGC CGAA ICUUUACC 2382 1068 AAGCAGAC C CACGUUCC608 GGAACGUG CUGAUGAG GCCGUUAGGC CGAA IUCUGCUU 2383 1069 AGCAGACC CACGUUCCC 609 GGGAACGU CUGAUGAG GCCGUUAGGC CGAA IGUCUGCU 2384 1070GCAGACCC A CGUUCCCA 610 UGGGAACG CUGAUGAG GCCGUUAGGC CGAA IGGUCUGC 23851076 CCACGUUC C CAACCUCU 611 AGAGGUUG CUGAUGAG GCCGUUAGGC CGAA IAACGUGG2386 1077 CACGUUCC C AACCUCUU 612 AAGAGGUU CUGAUGAG GCCGUUAGGC CGAAIGAACGUG 2387 1078 ACGUUCCC A ACCUCUUC 613 GAAGAGGU CUGAUGAGGCCGUUAGGC CGAA IGGAACGU 2388 1081 UUCCCAAC C UCUUCUCC 614 GGAGAAGACUGAUGAG GCCGUUAGGC CGAA IUUGGGAA 2389 1082 UCCCAACC U CUUCUCCC 615GGGAGAAG CUGAUGAG GCCGUUAGGC CGAA IGUUGGGA 2390 1084 CCAACCUC U UCUCCCUG616 CAGGGAGA CUGAUGAG GCCGUUAGGC CGAA IAGGUUGG 2391 1087 ACCUCUUC UCCCUGCAG 617 CUGCAGGG CUGAUGAG GCCGUUAGGC CGAA IAAGAGGU 2392 1089CUCUUCUC C CUGCAGCU 618 AGCUGCAG CUGAUGAG GCCGUUAGGC CGAA IAGAAGAG 23931090 UCUUCUCC C UGCAGCUU 619 AAGCUGCA CUGAUGAG GCCGUUAGGC CGAA IGAGAAGA2394 1091 CUUCUCCC U GCAGCUUU 620 AAAGCUGC CUGAUGAG GCCGUUAGGC CGAAIGGAGAAG 2395 1094 CUCCCUGC A GCUUUGUG 621 CACAAAGC CUGAUGAGGCCGUUAGGC CGAA ICAGGGAG 2396 1097 CCUGCAGC U UUGUGGUG 622 CACCACAACUGAUGAG GCCGUUAGGC CGAA ICUGCAGG 2397 1107 UGUGGUGC U GGCUUCCC 623GGGAAGCC CUGAUGAG GCCGUUAGGC CGAA ICACCACA 2398 1111 GUGCUGGC U UCCCCCUC624 GAGGGGGA CUGAUGAG GCCGUUAGGC CGAA ICCAGCAC 2399 1114 CUGGCUUC CCCCUCAAC 625 GUUGAGGG CUGAUGAG GCCGUUAGGC CGAA IAAGCCAG 2400 1115UGGCUUCC C CCUCAACC 626 GGUUGAGG CUGAUGAG GCCGUUAGGC CAGG IGAAGCCA 24011116 GGCUUCCC C CUCAACCA 627 UGGUUGAG CUGAUGAG GCCGUUAGGC CGAA IGGAAGCC2402 1117 GCUUCCCC C UCAACCAG 628 CUGGUUGA CUGAUGAG GCCGUUAGGC CGAAIGGGAAGC 2403 1118 CUUCCCCC U CAACCAGU 629 ACUGGUUG CUGAUGAGGCCGUUAGGC CGAA IGGGGAAG 2404 1120 UCCCCCUC A ACCAGUCU 630 AGACUGGUCUGAUGAG GCCGUUAGGC CGAA IAGGGGGA 2405 1123 CCCUCAAC C AGUCUGAA 631UUCAGACU CUGAUGAG GCCGUUAGGC CGAA IUUGAGGG 2406 1124 CCUCAACC A GUCUGAAG632 CUCCAGAC CUGAUGAG GCCGUUAGGC CGAA IGUUGAGG 2407 1128 AACCAGUC UGAAGUGCU 633 AGCACUUC CUGAUGAG GCCGUUAGGC CGAA IACUGGUU 2408 1136UGAAGUGC U GGCCUCUG 634 CAGAGGCC CUGAUGAG GCCGUUAGGC CGAA ICACUUCA 24091140 GUGCUGGC C UCUGUCGG 635 CCGACAGA CUGAUGAG GCCGUUAGGC CGAA ICCAGCAC2410 1141 UGCUGGCC U CUGUCGGA 636 UCCGACAG CUGAUGAG GCCGUUAGGC CGAAIGCCAGCA 2411 1143 CUGGCCUC U GUCGGAGG 637 CCUCCGAC CUGAUGAGGCCGUUAGGC CGAA IAGGCCAG 2412 1156 GAGGGAGC A UGAUCAUU 638 AAUGAUCACUGAUGAG GCCGUUAGGC CGAA ICUCCCUC 2413 1162 GCAUGAUC A UUGGAGGU 639ACCUCCAA CUGAUGAG GCCGUUAGGC CGAA IAUCAUGC 2414 1177 GUAUCGAC C ACUCGCUG640 CAGCGAGU CUGAUGAG GCCGUUAGGC CGAA IUCGAUAC 2415 1178 UAUCGACC ACUCGCUGU 641 ACAGCGAG CUGAUGAG GCCGUUAGGC CGAA IGUCGAUA 2416 1180UCGACCAC U CGCUGUAC 642 GUACAGCG CUGAUGAG GCCGUUAGGC CGAA IUGGUCGA 24171184 CCACUCGC U GUACACAG 643 CUGUGUAC CUGAUGAG GCCGUUAGGC CGAA ICGAGUGG2418 1189 CGCUGUAC A CAGGCAGU 644 ACUGCCUG CUGAUGAG GCCGUUAGGC CGAAIUACAGCG 2419 1191 CUGUACAC A GGCAGUCU 645 AGACUGCC CUGAUGAGGCCGUUAGGC CGAA IUGUACAG 2420 1195 ACACAGGC A GUCUCUGG 646 CCAGAGACCUGAUGAG GCCGUUAGGC CGAA ICCUGUGU 2421 1199 AGGCAGUC U CUGGUAUA 647UAUACCAG CUGAUGAG GCCGUUAGGC CGAA IACUGCCU 2422 1201 GCAGUCUC U GGUAUACA648 UGUAUACC CUGAUGAG GCCGUUAGGC CGAA IAGACUGC 2423 1209 UGGUAUAC ACCCAUCCG 649 CGGAUGGG CUGAUGAG GCCGUUAGGC CGAA IUAUACCA 2424 1211GUAUACAC C CAUCCGGC 650 GCCGGAUG CUGAUGAG GCCGUUAGGC CGAA IUGUAUAC 24251212 UAUACACC C AUCCGGCG 651 CGCCGGAU CUGAUGAG GCCGUCAGGC CGAA IGUGUAUA2426 1213 AUACACCC A UCCGGCGG 652 CCGCCGGA CUGAUGAG GCCGUUAGGC CGAAIGGUGUAU 2427 1216 CACCCAUC C GGCGGGAG 653 CUCCCGCC CUGAUGAGGCCGUUAGGC CGAA IAUGGGUG 2428 1243 AGGUGAUC A UUGUGCGG 654 CCGCACAACUGAUGAG GCCGUUAGGC CGAA IAUCACCU 2429 1261 UGGAGAUC A AUGGACAG 655CUGUCCAU CUGAUGAG GCCGUUAGGC CGAA IAUCUCCA 2430 1268 CAAUGGAC A GGAUCUGA656 UCAGAUCC CUGAUGAG GCCGUUAGGC CGAA IUCCAUUG 2431 1274 ACAGGAUC UGAAAAUGG 657 CCAUUUUC CUGAUGAG GCCGUUAGGC CGAA IAUCCUGU 2432 1285AAAUGGAC U CGAAGGAG 658 CUCCUUGC CUGAUGAG GCCGUUAGGC CGAA IUCCAUUU 24331288 UGGACUGC A AGGAGUAC 659 GUACUCCU CUGAUGAG GCCGUUAGGC CGAA ICAGUCCA2434 1297 AGGAGUAC A ACUAUGAC 660 GUCAUAGU CUGAUGAG GCCGUUAGGC CGAAIUACUCCU 2435 1300 AGUACAAC U AUGACAAG 661 CUUGUCAU CUGAUGAGGCCGUUAGGC CGAA IUUGUACU 2436 1306 ACUAUGAC A AGAGCAUU 662 AAUGCUCUCUGAUGAG GCCGUUAGGC CGAA IUCAUAGU 2437 1312 ACAAGAGC A UUGUGGAC 663GUCCACAA CUGAUGAG GCCGUUAGGC CGAA ICUCUUGU 2438 1321 UUGUGGAC A GUGGCACC664 GGUGCCAC CUGAUGAG GCCGUUAGGC CGAA IUCCACAA 2439 1327 ACAGUGGC ACCACCAAC 665 GUUGGUGG CUGAUGAG GCCGUUAGGC CGAA ICCACUGU 2440 1329AGUGGCAC C ACCAACCU 666 AGGUUGGU CUGAUGAG GCCGUUAGGC CGAA IUGCCACU 24411330 GUGGCACC A CCAACCUU 667 AAGGUUGG CUGAUGAG GCCGUUAGGC CGAA IGUGCCAC2442 1332 GGCACCAC C AACCUUCG 668 CGAAGGUU CUGAUGAG GCCGUUAGGC CGAAIUGGUGCC 2443 1333 GCACCACC A ACCUUCGU 669 ACGAAGGU CUGAUGAGGCCGUUAGGC CGAA IGUGGUGC 2444 1336 CCACCAAC C UUCGUUUG 670 CAAACGAACUGAUGAG GCCGUUAGGC CGAA IUUGGUGG 2445 1337 CACCAACC U UCGUUUGC 671GCAAACGA CUGAUGAG GCCGUUAGGC CGAA IGUUGGUG 2446 1346 UCGUUUGC C CAAGAAAG672 CUUUCUUG CUGAUGAG GCCGUUAGGC CGAA ICAAACGA 2447 1347 CGUUUGCC CAAGAAAGU 673 ACUUUCUU CUGAUGAG GCCGUUAGGC CGAA IGCAAACG 2448 1348GUUUGCCC A AGAAAGUG 674 CACUUUCU CUGAUGAG GCCGUUAGGC CGAA IGGCAAAC 24491365 UUUGAAGC U GCAGUCAA 675 UUGACUGC CUGAUGAG GCCGUUAGGC CGAA ICUUCAAA2450 1368 GAAGCUGC A GUCAAAUC 676 GAUUUGAC CUGAUGAG GCCGUUAGGC CGAAICAGCUUC 2451 1372 CUGCAGUC A AAUCCAUC 677 GAUGGAUC CUGAUGAGGCCGUUAGGC CGAA IACUGCAG 2452 1377 GUCAAAUC C AUCAAGGC 678 GCCUUGAUCUGAUGAG GCCGUUAGGC CGAA IAUUUGAC 2453 1378 UCAAAUCC A UCAAGGCA 679UGCCUUGA CUGAUGAG GCCGUUAGGC CGAA IGAUUUGA 2454 1381 AAUCCAUC A AGGCAGCC680 GGCUGCCU CUGAUGAG GCCGUUAGGC CGAA IAUGGAUU 2455 1386 AUCAAGGC AGCCUCCUC 681 GAGGAGGC CUGAUGAG GCCGUUAGGC CGAA ICCUUGAU 2456 1389AAGGCAGC C UCCUCCAC 682 GUGGAGGA CUGAUGAG GCCGUUAGGC CGAA ICUGCCUU 24571390 AGGCAGCC U CCUCCACG 683 CGUGGAGG CUGAUGAG GCCGUUAGGC CGAA IGCUGCCU2458 1392 GCAGCCUC C UCCACGGA 684 UCCGUGGA CUGAUGAG GCCGUUAGGC CGAAIAGGCUGC 2459 1393 CAGCCUCC U CCACGGAG 685 CUCCGUGG CUGAUGAGGCCGUUAGGC CGAA IGAGGCUG 2460 1395 GCCUCCUC C ACGGAGAA 686 UUCUCCGUCUGAUGAG GCCGUUAGGC CGAA IAGGAGGC 2461 1396 CCUCCUCC A CGGAGAAG 687CUUCUCCG CUGAUGAG GCCGUUAGGC CGAA IGAGGAGG 2462 1408 AGAAGUUC C CUGAUGGU688 ACCAUCAG CUGAUGAG GCCGUUAGGC CGAA IAACUUCU 2463 1409 GAAGUUCC CUGAUGGUU 689 AACCAUCA CUGAUGAG GCCGUUAGGC CGAA IGAACUUC 2464 1410AAGUUCCC U GAUGGUUU 690 AAACCAUC CUGAUGAG GCCGUUAGGC CGAA IGGAACUU 24651420 AUGGUUUC U GGCUAGGA 691 UCCUAGCC CUGAUGAG GCCGUUAGGC CGAA IAAACCAU2466 1424 UUUCUGGC U AGGAGAGC 692 GCUCUCCU CUGAUGAG CGGCUUAGGC CGAAICCAGAAA 2467 1433 AGGAGAGC A GCUGGUGU 693 ACACCAGC CUGAUGAGGCCGUUAGGC CGAA ICUCUCCU 2468 1436 AGAGCAGC U GGUGUGCU 694 AGCACACCCUGAUGAG GCCGUUAGGC CGAA ICUGCUCU 2469 1444 UGGUGUGC U GGCAAGCA 695UGCUUGCC CUGAUGAG GCCGUUAGGC CGAA ICACACCA 2470 1448 GUGCUGGC A AGCAGGCA696 UGCCUGCU CUGAUGAG GCCGUUAGGC CGAA ICCAGCAC 2471 1452 UGGCAAGC AGGCACCAC 697 GUGGUGCC CUGAUGAG GCCGUUAGGC CGAA ICUUGCCA 2472 1456AAGCAGGC A CCACCCCU 698 AGGGGUGG CUGAUGAG GCCGUUAGGC CGAA ICCUGCUU 24731458 GCAGGCAC C ACCCCUUG 699 CAAGGGGU CUGAUGAG GCCGUUAGGC CGAA IUGCCUGC2474 1459 CAGGCACC A CCCCUUGG 700 CCAAGGGG CUGAUGAG GCCGUUAGGC CGAAIGUGCCUG 2475 1461 GGCACCAC C CCUUGGAA 701 UUCCAAGG CUGAUGAGGCCGUUAGGC CGAA IUGGUGCC 2476 1462 GCACCACC C CUUGGAAC 702 GUUCCAAGCUGAUGAG GCCGUUAGGC CGAA IGUGGUGC 2477 1463 CACCACCC C UUGGAACA 703UGUUCCAA CUGAUGAG GCCGUUAGGC CGAA IGGUGGUG 2478 1464 ACCACCCC U UGGAACAU704 AUGUUCCA CUGAUGAG GCCGUUAGGC CGAA IGGGUGGU 2479 1471 CUUGGAAC AUUUUCCCA 705 UGGGAAAA CUGAUGAG GCCGUUAGGC CGAA IUUCCAAG 2480 1477ACAUUUUC C CAGUCAUC 706 GAUGACUG CUGAUGAG GCCGUUAGGC CGAA IAAAAUGU 24811478 CAUUUUCC C AGUCAUCU 707 AGAUGACU CUGAUGAG GCCGUUAGGC CGAA IGAAAAUG2482 1479 AUUUUCCC A GUCAUCUC 708 GAGAUGAC CUGAUGAG GCCGUUAGGC CGAAIGGAAAAU 2483 1483 UCCCAGUC A UCUCACUC 709 GAGUGAGA CUGAUGAGGCCGUUAGGC CGAA IACUGGGA 2484 1486 CAGUCAUC U CACUCUAC 710 GUAGAGUGCUGAUGAG GCCGUUAGGC CGAA IAUGACUG 2485 1488 GUCAUCUC A CUCUACCU 711AGGUAGAG CUGAUGAG GCCGUUAGGC CGAA IAGAUGAC 2486 1490 CAUCUCAC U CUACCUAA712 UUAGGUAG CUGAUGAG GCCGUUAGGC CGAA IUGAGAUG 2487 1492 UCUCACUC UACCUAAUG 713 CAUUAGGU CUGAUGAG GCCGUUAGGC CGAA IAGUGAGA 2488 1495CACUCUAC C UAAUGGGU 714 ACCCAUUA CUGAUGAG GCCGUUAGGC CGAA IUAGAGUG 24891496 ACUCUACC U AAUGGGUG 715 CACCCAUU CUGAUGAG GCCGUUAGGC CGAA IGUAGAGU2490 1512 GAGGUUAC C AACCAGUC 716 GACUGGUU CUGAUGAG GCCGUUAGGC CGAAIUAACCUC 2491 1513 AGGUUACC A ACCAGUCC 717 GGACUGGU CUGAUGAGGCCGUUAGGC CGAA IGUAACCU 2492 1516 UUACCAAC C AGUCCUUC 718 GAAGGACUCUGAUGAG GCCGUUAGGC CGAA IUUGGUAA 2493 1517 UACCAACC A GUCCUUCC 719GGAAGGAC CUGAUGAG GCCGUUAGGC CGAA IGUUGGUA 2494 1521 AACCAGUC C UUCCGCAU720 AUGCGGAA CUGAUGAG GCCGUUAGGC CGAA IACUGGUU 2495 1522 ACCAGUCC UUCCGCAUC 721 GAUGCGGA CUGAUGAG GCCGUUAGGC CGAA IGACUGGU 2496 1525AGUCCUUC C GCAUCACC 722 GGUGAUGC CUGAUGAG GCCGUUAGGC CGAA IAAGGACU 24971528 CCUUCCGC A UCACCAUC 723 GAUGGUGA CUGAUGAG GCCGUUAGGC CGAA ICGGAAGG2498 1531 UCCGCAUC A CCAUCCUU 724 AAGGAUGG CUGAUGAG GCCGUUAGGC CGAAIAUGCGGA 2499 1533 CGCAUCAC C AUCCUUCC 725 GGAAGGAU CUGAUGAGGCCGUUAGGC CGAA IUGAUGCG 2500 1534 GCAUCACC A UCCUUCCG 726 CGGAAGGACUGAUGAG GCCGUUAGGC CGAA IGUGAUGC 2501 1537 UCACCAUC C UUCCGCAG 727CUGCGGAA CUGAUGAG GCCGUUAGGC CGAA IAUGGUGA 2502 1538 CACCAUCC U UCCGCAGC728 GCUGCGGA CUGAUGAG GCCGUUAGGC CGAA IGAUGGUG 2503 1541 CAUCCUUC CGCAGCAAU 729 AUUGCUGC CUGAUGAG GCCGUUAGGC CGAA IAAGGAUG 2504 1544CCUUCCGC A GCAAUACC 730 GGUAUUGC CUGAUGAG GCCGUUAGGC CGAA ICGGAAGG 25051547 UCCGCAGC A AUACCUGC 731 GCAGGUAU CUGAUGAG GCCGUUAGGC CGAA ICUGCGGA2506 1552 AGCAAUAC C UGCGGCCA 732 UGGCCGCA CUGAUGAG GCCGUUAGGC CGAAIUAUUGCU 2507 1553 GCAAUACC U GCGGCCAG 733 CUGGCCGC CUGAUGAGGCCGUUAGGC CGAA IGUAUUGC 2508 1559 CCUGCGGC C AGUGGAAG 734 CUUCCACUCUGAUGAG GCCGUUAGGC CGAA ICCGCAGG 2509 1560 CUGCGGCC A GUGGAAGA 735UCUUCCAC CUGAUGAG GCCGUUAGGC CGAA IGCCGCAG 2510 1575 GAUGUGGC C ACGUCCCA736 UGGGACGU CUGAUGAG GCCGUUAGGC CGAA ICCACAUC 2511 1576 AUGUGGCC ACGUCCCAA 737 UUGGGACG CUGAUGAG GCCGUUAGGC CGAA IGCCACAU 2512 1581GCCACGUC C CAAGACGA 738 UCGUCUUG CUGAUGAG GCCGUUAGGC CGAA IACGUGGC 25131582 CCACGUCC C AAGACGAC 739 GUCGUCUU CUGAUGAG GCCGUUAGGC CGAA IGACGUGG2514 1583 CACGUCCC A AGACGACU 740 AGUCGUCU CUGAUGAG GCCGUUAGGC CGAAIGGACGUG 2515 1591 AAGACGAC U GUUACAAG 741 CUUGUAAC CUGAUGAGGCCGUUAGGC CGAA IUCGUCUU 2516 1597 ACUGUUAC A AGUUUGCC 742 GGCAAACUCUGAUGAG GCCGUUAGGC CGAA IUAACAGU 2517 1605 AAGUUUGC C AUCUCACA 743UGUGAGAU CUGAUGAG GCCGUUAGGC CGAA ICAAACUU 2518 1606 AGUUUGCC A UCUCACAG744 CUGUGAGA CUGAUGAG GCCGUUAGGC CGAA IGCAAACU 2519 1609 UUGCCAUC UCACAGUCA 745 UGACUGUG CUGAUGAG GCCGUUAGGC CGAA IAUGGCAA 2520 1611GCCAUCUC A CAGUCAUC 746 GAUGACUG CUGAUGAG GCCGUUAGGC CGAA IAGAUGGC 25211613 CAUCUCAC A GUCAUCCA 747 UGGAUGAC CUGAUGAG GCCGUUAGGC CGAA IUGAGAUG2522 1617 UCACAGUC A UCCACGGG 748 CCCGUGGA CUGAUGAG GCCGUUAGGC CGAAIACUGUGA 2523 1620 CAGUCAUC C ACGGGCAC 749 GUGCCCGU CUGAUGAGGCCGUUAGGC CGAA IAUGACUG 2524 1621 AGUCAUCC A CGGGCACU 750 AGUGCCCGCUGAUGAG GCCGUUAGGC CGAA IGAUGACU 2525 1627 CCACGGGC A CUGUUAUG 751CAUAACAG CUGAUGAG GCCGUUAGGC CGAA ICCCGUGG 2526 1629 ACGGGCAC U GUUAUGGG752 CCCAUAAC CUGAUGAG GCCGUUAGGC CGAA IUGCCCGU 2527 1641 AUGGGAGC UGUUAUCAU 753 AUGAUAAC CUGAUGAG GCCGUUAGGC CGAA ICUCCCAU 2528 1648CUGUUAUC A UGGAGGGC 754 GCCCUCCA CUGAUGAG GCCGUUAGGC CGAA IAUAACAG 25291657 UGGAGGGC U UCUACGUU 755 AACGUAGA CUGAUGAG GCCGUUAGGC CGAA ICCCUCCA2530 1660 AGGGCUUC U ACGUUGUC 756 GACAACGU CUGAUGAG GCCGUUAGGC CGAAIAAGCCCU 2531 1669 ACGUUGUC U UUGAUCGG 757 CCGAUCAA CUGAUGAGGCCGUUAGGC CGAA IACAACGU 2532 1680 GAUCGGGC C CGAAAACG 758 CGUUUUCGCUGAUGAG GCCGUUAGGC CGAA ICCCGAUC 2533 1681 AUCGGGCC C GAAAACGA 759UCGUUUUC CUGAUGAG GCCGUUAGGC CGAA IGCCCGAU 2534 1696 GAAUUGGC U UUGCUGUC760 GACAGCAA CUGAUGAG GCCGUUAGGC GCAA ICCAAUUC 2535 1701 GGCUUUGC UGUCAGCGC 761 GCGCUGAC CUGAUGAG GCCGUUAGGC CGAA ICAAAGCC 2536 1705UUGCUGUC A GCGCUUGC 762 GCAAGCGC CUGAUGAG GCCGUUAGGC CGAA IACAGCAA 25371710 GUCAGCGC U UGCCAUGU 763 ACAUGGCA CUGAUGAG GCCGUUAGGC CGAA ICGCUGAC2538 1714 GCGCUUGC C AUGUGCAC 764 GUGCACAU CUGAUGAG GCCGUUAGGC CGAAICAAGCGC 2539 1715 CGCUUGCC A UGUGCACG 765 CGUGCACA CUGAUGAGGCCGUUAGGC CGAA IGCAAGCG 2540 1721 CCAUGUGC A CGAUGAGU 766 ACUCAUCGCUGAUGAG GCCGUUAGGC CGAA ICACAUGG 2541 1732 AUGAGUUC A GGACGGCA 767UGCCGUCC CUGAUGAG GCCGUUAGGC CGAA IAACUCAU 2542 1740 AGGACGGC A GCGGUGGA768 UCCACCGC CUGAUGAG GCCGUUAGGC CGAA ICCGUCCU 2543 1753 UGGAAGGC CCUUUUGUC 769 GACAAAAG CUGAUGAG GCCGUUAGGC CGAA ICCUUCCA 2544 1754GGAAGGCC C UUUUGUCA 770 UGACAAAA CUGAUGAG GCCGUUAGGC CGAA IGCCUUCC 25451755 GAAGGCCC U UUUGUCAC 771 GUGACAAA CUGAUGAG GCCGUUAGGC CGAA IGGCCUUC2546 1762 CUUUUGUC A CCUUGGAC 772 GUCCAAGG CUGAUGAG GCCGUUAGGC CGAAIACAAAAG 2547 1764 UUUGUCAC C UUGGACAU 773 AUGUCCAA CUGAUGAGGCCGUUAGGC CGAA IUGACAAA 2548 1765 UUGUCACC U UGGACAUG 774 CAUGUCCACUGAUGAG GCCGUUAGGC CGAA IGUGACAA 2549 1771 CCUUGGAC A UGGAAGAC 775GUCUUCCA CUGAUGAG GCCGUUAGGC CGAA IUCCAAGG 2550 1780 UGGAAGAC U GUGGCUAC776 GUAGCCAC CUGAUGAG GCCGUUAGGC CGAA IUCUUCCA 2551 1786 ACUGUGGC UACAACAUU 777 AAUGUUGU CUGAUGAG GCCGUUAGGC CGAA ICCACAGU 2552 1789GUGGCUAC A ACAUUCCA 778 UGGAAUGU CUGAUGAG GCCGUUAGGC CGAA IUAGCCAC 25531792 GCUACAAC A UUCCACAG 779 CUGUGGAA CUGAUGAG GCCGUUAGGC CGAA IUUGUAGC2554 1796 CAACAUUC C ACAGACAG 780 CUGUCUGU CUGAUGAG GCCGUUAGGC CGAAIAAUGUUG 2555 1797 AACAUUCC A CAGACAGA 781 UCUGUCUG CUGAUGAGGCCGUUAGGC CGAA IGAAUGUU 2556 1799 CAUUCCAC A GACAGAUG 782 CAUCUGUCCUGAUGAG GCCGUUAGGC CGAA IUGGAAUG 2557 1803 CCACAGAC A GAUGAGUC 783GACUCAUC CUGAUGAG GCCGUUAGGC CGAA IUCUGUGG 2558 1812 GAUGAGUC A ACCCUCAU784 AUGAGGGU CUGAUGAG GCCGUUAGGC CGAA IACUCAUC 2559 1815 GAGUCAAC CCUCAUGAC 785 GUCAUGAG CUGAUGAG GCCGUUAGGC CGAA IUUGACUC 2560 1816AGUCAACC C UCAUGACC 786 GGUCAUGA CUGAUGAG GCCGUUAGGC CGAA IGUUGACU 25611817 GUCAACCC U CAUGACCA 787 UGGUCAUG CUGAUGAG GCCGUUAGGC CGAA IGGUUGAC2562 1819 CAACCCUC A UGACCAUA 788 UAUGGUCA CUGAUGAG GCCGUUAGGC CGAAIAGGGUUG 2563 1824 CUCAUGAC C AUAGCCUA 789 UAGGCUAU CUGAUGAGGCCGUUAGGC CGAA IUCAUGAG 2564 1825 UCAUGACC A UAGCCUAU 790 AUAGGCUACUGAUGAG GCCGUUAGGC CGAA IGUCAUGA 2565 1830 ACCAUAGC C UAUGUCAU 791AUGACAUA CUGAUGAG GCCGUUAGGC CGAA ICUAUGGU 2566 1831 CCAUAGCC U AUGUCAUG792 CAUGACAU CUGAUGAE GCCGUUAGGC CGAA IGCUAUGG 2567 1837 CCUAUGUC AUGGCUGCC 793 GGCAGCCA CUGAUGAG GCCGUUAGGC CGAA IACAUAGG 2568 1842GUCAUGGC U CGGAUCUG 794 CAGAUGGC CUGAUGAG GCCGUUAGGC CGAA ICCAUGAC 25691845 AUGGCUGC C AUCUGCGC 795 GCGCAGAU CUGAUGAG GCCGUUAGGC CGAA ICAGCCAU2570 1846 UGGCUGCC A UCUGCGCC 796 GGCGCAGA CUGAUGAG GCCGUUAGGC CGAAIGCAGCCA 2571 1849 CUGCCAUC U GCGCCCUC 797 GAGGGCGC CUGAUGAGGCCGUUAGGC CGAA IAUGGCAG 2572 1854 AUCUGCGC C CUCUUCAU 798 AUGAAGAGCUGAUGAG GCCGUUAGGC CGAA ICGCAGAU 2573 1855 UCUGCGCC C UCCUCAUG 799CAUGAAGA CUGAUGAG GCCGUUAGGC CGAA IGCGCAGA 2574 1856 CUGCGCCC U CUUCAUGC800 GCAUGAAG CUGAUGAG GCCGUUAGGC CGAA IGGCGCAG 2575 1858 GCGCCCUC UUCAUGCUG 801 CAGCAUGA CUGAUGAG GCCGUUAGGC CGAA IAGGGCGC 2576 1861CCCUCUUC A UGCUGCCA 802 UGGCAGCA CUGAUGAG GCCGUUAGGC CGAA IAAGAGGG 25771865 CUUCAUGC U GCCACUCU 803 AGAGUGGC CUGAUGAG GCCGUUAGGC CGAA ICAUGAAG2578 1868 CAUGCUGC C ACUCUGCC 804 GGCAGAGU CUGAUGAG GCCGUUAGGC CGAAICAGCAUG 2579 1869 AUGCUGCC A CUCUGCCU 805 AGGCAGAG CUGAUGAGGCCGUUAGGC CGAA IGCAGCAU 2580 1871 GCUGCCAC U CUGCCUCA 806 UGAGGCAGCUGAUGAG GCCGUUAGGC CGAA IUGGCAGC 2581 1873 UGCCACUC U GCCUCAUG 807CAUGAGGC CUGAUGAG GCCGUUAGGC CGAA IAGUGGCA 2582 1876 CACUCUGC C UCAUGGUG808 CACCAUGA CUGAUGAG GCCGUUAGGC CGAA ICAGAGUG 2583 1877 ACUCUGCC UCAUGGUGU 809 ACACCAUG CUGAUGAG GCCGUUAGGC CGAA IGCAGAGU 2584 1879UCUGCCUC A UGGUGUGU 810 ACACACCA CUGAUGAG GCCGUUAGGC CGAA IAGGCAGA 25851889 GGUGUGUC A GUGGCGCU 811 AGCGCCAC CUGAUGAG GCCGUUAGGC CGAA IACACACC2586 1897 AGUGGCGC U GCCUCCGC 812 GCGGAGGC CUGAUGAG GCCGUUAGGC CGAAICGCCACU 2587 1900 GGCGCUGC C UCCGCUGC 813 GCAGCGGA CUGAUGAGGCCGUUAGGC CGAA ICAGCGCC 2588 1901 GCGCUGCC U CCGCUGCC 814 GGCAGCGGCUGAUGAG GCCGUUAGGC CGAA IGCAGCGC 2589 1903 GCUGCCUC C GCUGCCUG 815CAGGCAGC CUGAUGAG GCCGUUAGGC CGAA IAGGCAGC 2590 1906 GCCUCCGC U GCCUGCGC816 GCGCAGGC CUGAUGAG GCCGUUAGGC CGAA ICGGAGGC 2591 1909 UCCGCUGC CUGCGCCAG 817 CUGGCGCA CUGAUGAG GCCGUUAGGC CGAA ICAGCGGA 2592 1910CCGCUGCC U GCGCCAGC 818 GCUGGCGC CUGAUGAG GCCGUUAGGC CGAA IGCAGCGG 25931915 GCCUGCGC C AGCAGCAU 819 AUGCUGCU CUGAUGAG GCCGUUAGGC CGAA ICGCAGGC2594 1916 CCUGCGCC A GCAGCAUG 820 CAUGCUGC CUGAUGAG GCCGUUAGGC CGAAIGCGCAGG 2595 1919 GCGCCAGC A GCAUGAUG 821 CAUCAUGC CUGAUGAGGCCGUUAGGC CGAA ICUGGCGC 2596 1922 CCAGCAGC A UGAUGACU 822 AGUCAUCACUGAUGAG GCCGUUAGGC CGAA ICUGCUGG 2597 1930 AUGAUGAC U UUGCUGAU 823AUCAGCAA CUGAUGAG GCCGUUAGGC CGAA IUCAUCAU 2598 1935 GACUUUGC U GAUGACAU824 AUGUCAUC CUGAUGAG GCCGUUAGGC CGAA ICAAAGUC 2599 1942 CUGAUGAC AUCUCCCUG 825 CAGGGAGA CUGAUGAG GCCGUUAGGC CGAA IUCAUCAG 2600 1945AUGACAUC U CCCUGCUG 826 CAGCAGGG CUGAUGAG GCCGUUAGGC CGAA IAUGUCAU 26011947 GACAUCUC C CUGCUGAA 827 UUCAGCAG CUGAUGAG GCCGUUAGGC CGAA IAGAUGUC2602 1948 ACAUCUCC C UGCUGAAG 828 CUUCAGCA CUGAUGAG GCCGUUAGGC CGAAIGAGAUGU 2603 1949 CAUCUCCC U GCUGAAGU 829 ACUUCAGC CUGAUGAGGCCGUUAGGC CGAA IGGAGAUG 2604 1952 CUCCCUGC U GAAGUGAG 830 CUCACUUCCUGAUGAG GCCGUUAGGC CGAA ICAGGGAG 2605 1966 GAGGAGGC C CAUGGGCA 831UGCCCAUG CUGAUGAG GCCGUUAGGC CGAA ICCUCCUC 2606 1967 AGGAGGCC C AUGGGCAG832 CUGCCCAU CUGAUGAG GCCGUUAGGC CGAA IGCCUCCU 2607 1968 GGAGGCCC AUGGGCAGA 833 UCUGCCCA CUGAUGAG GCCGUUAGGC CGAA IGGCCUCC 2608 1974CCAUGGGC A GAAGAUAC 834 CUAUCUUC CUGAUGAG GCCGUUAGGC CGAA ICCCAUGG 26091989 AGAGAUUC C CCUGGACC 835 GGUCCAGG CUGAUGAG GCCGUUAGGC CGAA IAAUCUCU2610 1990 GAGAUUCC C CUGGACCA 836 UGGUCCAG CUGAUGAG GCCGUUAGGC CGAAIGAAUCUC 2611 1991 AGAUUCCC C UGGACCAC 837 GUGGUCCA CUGAUGAGGCCGUUAGGC CGAA IGGAAUCU 2612 1992 GAUUCCCC U GGACCACA 838 UGUGGUCCCUGAUGAG GCCGUUAGGC CGAA IGGGAAUC 2613 1997 CCCUGGAC C ACACCUCC 839GGAGGUGU CUGAUGAG GCCGUUAGGC CGAA IUCCAGGG 2614 1998 CCUGGACC A CACCUCCG840 CGGAGGUG CUGAUGAG GCCGUUAGGC CGAA IGUCCAGG 2615 2000 UGGACCAC ACCUCCGUG 841 CACGGAGG CUGAUGAG GCCGUUAGGC CGAA IUGGUCCA 2616 2002GACCACAC C UCCGUGGU 842 ACCACGGA CUGAUGAG GCCGUUAGGC CGAA IUGUGGUC 26172003 ACCACACC U CCGUGGUU 843 AACCACGG CUGAUGAG GCCGUUAGGC CGAA IGUGUGGU2618 2005 CACACCUC C GUGGUUCA 844 UGAACCAC CUGAUGAG GCCGUUAGGC CGAAIAGGUGUG 2619 2013 CGUGGUUC A CUUUGGUC 845 GACCAAAG CUGAUGAGGCCGUUAGGC CGAA IAACCACG 2620 2015 UGGUUCAC U UUGGUCAC 846 GUGACCAACUGAUGAG GCCGUUAGGC CGAA IUGAACCA 2621 2022 CUUUGGUC A CAAGUAGG 847CCUACUUG CUGAUGAG GCCGUUAGGC CGAA IACCAAAG 2622 2024 UUGGUCAC A AGUAGGAG848 CUCCUACU CUGAUGAG GCCGUUAGGC CGAA IUGACCAA 2623 2035 UAGGAGAC ACAGAUGGC 849 GCCAUCUG CUGAUGAG GCCGUUAGGC CGAA IUCUCCUA 2624 2037GGAGACAC A GAUGGCAC 850 GUGCCAUC CUGAUGAG GCCGUUAGGC CGAA IUGUCUCC 26252044 CAGAUGGC A CCUGUGGC 851 GCCACAGG CUGAUGAG GCCGUUAGGC CGAA ICCAUCUG2626 2046 GAUGGCAC C UGUGGCCA 852 UGGCCACA CUGAUGAG GCCGUUAGGC CGAAIUGCCAUC 2627 2047 AUGGCACC U GUGGCCAG 853 CUGGCCAC CUGAUGAGGCCGUUAGGC CGAA IGUGCCAU 2628 2053 CCUGUGGC C AGAGCACC 854 GGUGCUCUCUGAUGAG GCCGUUAGGC CGAA IGGACAGG 2629 2054 CUGUGGCC A GAGCACCU 855AGGUGCUC CUGAUGAG GCCGUUAGGC CGAA IGCCACAG 2630 2059 GCCAGAGC A CCUCAGGA856 UCCUGAGG CUGAUGAG GCCGUUAGGC CGAA ICUCUGGC 2631 2061 CAGAGCAC CUCAGGACC 857 GGUCCUGA CUGAUGAG GCCGUUAGGC CGAA IUGCUCUG 2632 2052AGAGCACC U CAGGACCC 858 GGGUCCUG CUGAUGAG GCCGUUAGGC CGAA IGUGCUCU 26332064 AGCACCUC A GGACCCUC 859 GAGGGUCC CUGAUGAG GCCGUUAGGC CGAA IAGGUGCU2634 2069 CUCAGGAC C CUCCCCAC 860 GUGGGGAG CUGAUGAG GCCGUUAGGC CGAAIUCCUGAG 2635 2070 UCAGGACC C UCCCCACC 861 GGUGGGGA CUGAUGAGGCCGUUAGGC CGAA IGUCCUGA 2636 2071 CAGGACCC U CCCCACCC 862 GGGUGGGGCUGAUGAG GCCGUUAGGC CGAA IGGUCCUG 2637 2073 GGACCCUC C CCACCCAC 863GUGGGUGG CUGAUGAG GCCGUUAGGC CGAA IAGGGUCC 2638 2074 GACCCUCC C CACCCACC864 GGUGGGUG CUGAUGAG GCCGUUAGGC CGAA IGAGGGUC 2639 2075 ACCCUCCC CACCCACCA 865 UGGUGGGU CUGAUGAG GCCGUUAGGC CGAA IGGAGGGU 2640 2076CCCUCCCC A CCCACCAA 866 UUGGUGGG CUGAUGAG GCCGUUAGGC CGAA IGGGAGGG 26412078 CUCCCCAC C CACCAAAU 867 AUUUGGUG CUGAUGAG GCCGUUAGGC CGAA IUGGGGAG2642 2079 UCCCCACC C ACCAAAUG 868 CAUUUGGU CUGAUGAG GCCGUUAGGC CGAAIGUGGGGA 2643 2080 CCCCACCC A CCAAAUGC 869 GCAUUUGG CUGAUGAGGCCGUUAGGC CGAA IGGUGGGG 2644 2082 CCACCCAC C AAAUGCCU 870 AGGCAUUUCUGAUGAG GCCGUUAGGC CGAA IUGGGUGG 2645 2083 CACCCACC A AAUGCCUC 871GAGGCAUU CUGAUGAG GCCGUUAGGC CGAA IGUGGGUG 2646 2089 CCAAAUGC C UCUGCCUU872 AAGGCAGA CUGAUGAG GCCGUUAGGC CGAA ICAUUUGG 2647 2090 CAAAUGCC UCUGCCUUG 873 CAAGGCAG CUGAUGAG GCCGUUAGGC CGAA IGCAUUUG 2648 2092AAUGCCUC U GCCUUGAU 874 AUCAAGGC CUGAUGAG GCCGUUAGGC CGAA IAGGCAUU 26492095 GCCUCUGC C CUGAUGGA 875 UCCAUCAA CUGAUGAG GCCGUUAGGC CGAA ICAGAGGC2650 2096 CCUCUGCC U UGAUGGAG 876 CUCCAUCA CUGAUGAG GCCGUUAGGC CGAAIGCAGAGG 2651 2116 GAAAAGGC U GGCAAGGU 877 ACCUUGCC CUGAUGAGGCCGUUAGGC CGAA ICCUUUUC 2652 2120 AGGCUGGC A AGGUGGGU 878 ACCCACCUCUGAUGAG GCCGUUAGGC CGAA ICCAGCCU 2653 2131 GUGGGUUC C AGGGACUG 879CAGUCCCU CUGAUGAG GCCGUUAGGC CGAA IAACCCAC 2654 2132 UGGGUUCC A GGGACUGU880 ACAGUCCC CUGAUGAG GCCGUUAGGC CGAA IGAACCCA 2655 2138 CCAGGGAC UGUACCUGU 881 ACAGGUAC CUGAUGAG GCCGUUAGGC CGAA IUCCCUGG 2656 2143GACUGUAC C UGUAGGAA 882 UUCCUACA CUGAUGAG GCCGUUAGGC CGAA IUACAGUC 26572144 ACUGUACC U GUAGGAAA 883 UUUCCUAC CUGAUGAG GCCGUUAGGC CGAA IGUACAGU2658 2154 UAGGAAAC A GAAAAGAG 884 CUCUUUUC CUGAUGAG GCCGUUAGGC CGAAIUUUCCUA 2659 2174 AAAGAAGC A CUCUGCUG 885 CAGCAGAG CUGAUGAGGCCGUUAGGC CGAA ICUUCUUU 2660 2176 AGAAGCAC U CUGCUGGC 886 GCCAGCAGCUGAUGAG GCCGUUAGGC CGAA IUGCUUCU 2661 2178 AAGCACUC U GCUGGCGG 887CCGCCAGC CUGAUGAG GCCGUUAGGC CGAA IAGUGCUU 2662 2181 CACUCUGC U GGCGGGAA888 UUCCCGCC CUGAUGAG GCCGUUAGGC CGAA ICAGAGUG 2663 2193 GGGAAUAC UCUUGGUCA 889 UGACCAAG CUGAUGAG GCCGUUAGGC CGAA IUAUUCCC 2664 2195GAAUACUC U UGGUCACC 890 GGUGACCA CUGAUGAG GCCGUUAGGC CGAA IAGUAUUC 26652201 UCUUGGUC A CCUCAAAU 891 AUUUGAGG CUGAUGAG GCCGUUAGGC CGAA IACCAAGA2666 2203 UUGGUCAC C UCAAAUUU 892 AAAUUUGA CUGAUGAG GCCGUUAGGC CGAAIUGACCAA 2667 2204 UGGUCACC U CAAAUUUA 893 UAAAUUUG CUGAUGAGGCCGUUAGGC CGAA IGUGACCA 2668 2206 GUCACCUC A AAUUUAAG 894 CUUAAAUUCUGAUGAG GCCGUUAGGC CGAA IAGGUGAC 2669 2226 GGAAAUUC U GCUGCUUG 895CAAGCAGC CUGAUGAG GCCGUUAGGC CGAA IAAUUUCC 2670 2229 AAUUCUGC U GCUUGAAA896 UUUCAAGC CUGAUGAG GCCGUUAGGC CGAA ICAGAAUU 2671 2232 UCUGCUGC UUGAAACUU 897 AAGUUUCA CUGAUGAG GCCGUUAGGC CGAA ICAGCAGA 2672 2239CUUGAAAC U UCAGCCCU 898 AGGGCUGA CUGAUGAG GCCGUUAGGC CGAA IUUUCAAG 26732242 GAAACUUC A GCCCUGAA 899 UUCAGGGC CUGAUGAG GCCGUUAGGC CGAA IAAGUUUC2674 2245 ACUUCAGC C CUGAACCU 900 AGGUUCAG CUGAUGAG GCCGUUAGGC CGAAICUGAAGU 2675 2246 CUUCAGCC C UGAACCUU 901 AAGGUUCA CUGAUGAGGCCGUUAGGC CGAA IGCUGAAG 2676 2247 UUCAGCCC U GAACCUUU 902 AAAGGUUCCUGAUGAG GCCGUUAGGC CGAA IGGCUGAA 2677 2252 CCCUGAAC C UUUGUCCA 902UGGACAAA CUGAUGAG GCCGUUAGGC CGAA IUUCAGGG 2678 2253 CCUGAACC U UUGUCCAC904 GUGGACAA CUGAUGAG GCCGUUAGGC CGAA IGUUCAGG 2679 2259 CCUUUGUC CACCAUUCC 905 GGAAUGGU CUGAUGAG GCCGUUAGGC CGAA IACAAAGG 2680 2260CUUUGUCC A CCAUUCCU 906 AGGAAUGG CUGAUGAG GCCGUUAGGC CGAA IGACAAAG 26812262 UUGUCCAC C AUUCCUUU 907 AAAGGAAU CUGAUGAG GCCGUUAGGC CGAA IUGGACAA2682 2263 UGUCCACC A UUCCUUUA 908 UAAAGGAA CUGAUGAG GCCGUUAGGC CGAAIGUGGACA 2683 2267 CACCAUUC C UUUAAAUU 909 AAUUUAAA CUGAUGAGGCCGUUAGGC CGAA IAAUGGUG 2684 2268 ACCAUUCC U UUAAAUUC 910 GAAUUUAACUGAUGAG GCCGUUAGGC CGAA IGAAUGGU 2685 2277 UUAAAUUC U CCAACCCA 911UGGGUUGG CUGAUGAG GCCGUUAGGC CGAA IAAUUUAA 2686 2279 AAAUUCUC C AACCCAAA912 UUUGGGUU CUGAUGAG GCCGUUAGGC CGAA IAGAAUUU 2687 2280 AAUUCUCC AACCCAAAG 913 CUUUGGGU CUGAUGAG GCCGUUAGGC CGAA IGAGAAUU 2688 2283UCUCCAAC C CAAAGUAU 914 AUACUUUG CUGAUGAG GCCGUUAGGC CGAA IUUGGAGA 26892284 CUCCAACC C AAAGUAUU 915 AAUACUUU CUGAUGAG GCCGUUAGGC CGAA IGUUGGAG2690 2285 UCCAACCC A AAGUAUUC 916 GAAUACUU CUGAUGAG GCCGUUAGGC CGAAIGGUUGGA 2691 2294 AAGUAUUC U UCUUUUCU 917 AGAAAAGA CUGAUGAGGCCGUUAGGC CGAA IAAUACUU 2692 2297 UAUUCUUC U UUUCUUAG 918 CUAAGAAACUGAUGAG GCCGUUAGGC CGAA IAAGAAUA 2693 2302 UUCUUUUC U UAGUUUCA 919UGAAACUA CUGAUGAG GCCGUUAGGC CGAA IAAAAGAA 2694 2310 UUAGUUUC A GAAGUACU920 AGUACUUC CUGAUGAG GCCGUUAGGC CGAA IAAACUAA 2695 2318 AGAAGUAC UGGCAUCAC 921 GUGAUGCC CUGAUGAG GCCGUUAGGC CGAA IUACUUCU 2696 2322GUACUGGC A UCACACGC 922 GCGUGUGA CUGAUGAG GCCGUUAGGC CGAA ICCAGUAC 26972325 CUGGCAUC A CACGCAGG 923 CCUGCGUG CUGAUGAG GCCGUUAGGC CGAA IAUGCCAG2698 2327 GGCAUCAC A CGCAGGUU 924 AACCUGCG CUGAUGAG GCCGUUAGGC CGAAIUGAUGCC 2699 2331 UCACACGC A GGUUACCU 925 AGGUAACC CUGAUGAGGCCGUUAGGC CGAA ICGUGUGA 2700 2338 CAGGUUAC C UUGGCGUG 926 CACGCCAACUGAUGAG GCCGUUAGGC CGAA IUAACCUG 2701 2339 AGGUUACC U UGGCGUGU 927ACACGCCA CUGAUGAG GCCGUUAGGC CGAA IGUAACCU 2702 2351 CGUGUGUC C CUGUGGUA928 UACCACAG CUGAUGAG GCCGUUAGGC CGAA IACACACG 2703 2352 GUGUGUCC CUGUGGUAC 929 GUACCACA CUGAUGAG GCCGUUAGGC CGAA IGACACAC 2704 2353UGUGUCCC U GUGGUACC 930 GGUACCAC CUGAUGAG GCCGUUAGGC CGAA IGGACACA 27052361 UGUGGUAC C CUGGCAGA 931 UCUGCCAG CUGAUGAG GCCGUUAGGC CGAA IUACCACA2706 2362 GUGGUACC C UGGCAGAG 932 CUCUGCCA CUGAUGAG GCCGUUAGGC CGAAIGUACCAC 2707 2363 UGGUACCC U GGCAGAGA 933 UCUCUGCC CUGAUGAGGCCGUUAGGC CGAA IGGUACCA 2708 2367 ACCCUGGC A GAGAAGAG 934 CUCUUCUCCUGAUGAG GCCGUUAGGC CGAA ICCAGGGU 2709 2378 GAAGAGAC C AAGCUUGU 935ACAAGCUU CUGAUGAG GCCGUUAGGC CGAA IUCUCUUC 2710 2379 AAGAGACC A AGCUUGUU936 AACAAGCU CUGAUGAG GCCGUUAGGC CGAA IGUCUCUU 2711 2383 GACCAAGC UUGUUUCCC 937 GGGAAACA CUGAUGAG GCCGUUAGGC CGAA ICUUGGUC 2712 2390CUUGUUUC C CUGCUGGC 938 GCCAGCAG CUGAUGAG GCCGUUAGGC CGAA IAAACAAG 27132391 UUGUUUCC C UGCUGGCC 939 GGCCAGCA CUGAUGAG GCCGUUAGGC CGAA IGAAACAA2714 2392 UGUUUCCC U GCUGGCCA 940 UGGCCAGC CUGAUGAG GCCGUUAGGC CGAAIGGAAACA 2715 2395 UUCCCUGC U GGCCAAAG 941 CUUUGGCC CUGAUGAGGCCGUUAGGC CGAA ICAGGGAA 2716 2399 CUGCUGGC C AAAGUCAG 942 CUGACUUUCUGAUGAG GCCGUUAGGC CGAA ICCAGCAG 2717 2400 UGCUGGCC A AAGUCAGU 943ACUGACUU CUGAUGAG GCCGUUAGGC CGAA IGCCAGCA 2718 2406 CCAAAGUC A GUAGGAGA944 UCUCCUAC CUGAUGAG GCCGUUAGGC CGAA IACUUUGG 2719 2421 GAGGAUGC ACAGUUUGC 945 GCAAACUG CUGAUGAG GCCGUUAGGC CGAA ICAUCCUC 2720 2423GGAUGCAC A GUUUGCUA 946 UAGCAAAC CUGAUGAG GCCGUUAGGC CGAA IUGCAUCC 27212430 CAGUUUGC U AUUUGCUU 947 AAGCAAAU CUGAUGAG GCCGUUAGGC CGAA ICAAACUG2722 2437 CUAUUUGC U UUAGAGAC 948 GUCUCUAA CUGAUGAG GCCGUUAGGC CGAAICAAAUAG 2723 2446 UUAGAGAC A GGGACUGU 949 ACAGUCCC CUGAUGAGGCCGUUAGGC CGAA IUCUCUAA 2724 2452 ACAGGGAC U GUAUAAAC 950 GUUUAUACCUGAUGAG GCCGUUAGGC CGAA IUCCCUGU 2725 2461 GUAUAAAC A AGCCUAAC 951GUUAGGCU CUGAUGAG GCCGUUAGGC CGAA IUUUAUAC 2726 2465 AAACAAGC C UAACAUUG952 CAAUGUUA CUGAUGAG GCCGUUAGGC CGAA ICUUGUUU 2727 2466 AACAAGCC UAACAUUGG 953 CCAAUGUU CUGAUGAG GCCGUUAGGC CGAA IGCUUGUU 2728 2470AGCCUAAC A UUGGUGCA 954 UGCACCAA CUGAUGAG GCCGUUAGGC CGAA IUUAGGCU 27292478 AUUGGUGC A AAGAUUGC 955 GCAAUCUU CUGAUGAG GCCGUUAGGC CGAA ICACCAAU2730 2487 AAGAUUGC C UCUUGAAU 956 AUUCAAGA CUGAUGAG GCCGUUAGGC CGAAICAAUCUU 2731 2488 AGAUUGCC U CUUGAAUU 957 AAUUCAAG CUGAUGAGGCCGUUAGGC CGAA IGCAAUCA 2732 2490 AUUGCCUC U UGAAUUAA 958 UUAAUUCACUGAUGAG GCCGUUAGGC CGAA IAGGCAAU 2733 2509 AAAAAAAC U AGAAAAAA 959UUUUUUCU CUGAUGAG GCCGUUAGGC CGAA IUUUUUUU 2734

[0306] TABLE V Human BACE G-cleaver Ribozyme and Target Sequence PosSubstrate Seq ID G-cleaver Seq ID 11 ACGCGUCC G CAGCCCGC 960 GCGGGCUGUGAUG GCAUGCACUAUGC GCG GGACGCGU 2735 18 CGCAGCCC G CCCGGGAG 961CUCCCGGG UGAUG GCAUGCACUAUGC GCG GGGCUGCG 2736 29 CGGGAGCU G CGAGCCGC962 GCGGCUCG UGAUG GCAUGCACUAUGC GCG AGCUCCCG 2737 31 GGAGCUGC GAGCCGCGA 963 UCGCGGCU UGAUG GCAUGCACUAUGC GCG GCAGCUCC 2738 36 UGCGAGCCG CGAGCUGG 964 CCAGCUCG UGAUG GCAUGCACUAUGC GCG GGCUCGCA 2739 38CGAGCCGC G AGCUGGAU 965 AUCCAGCU UGAUG GCAUGCACUAUGC GCG GCGGCUCG 274058 GGUGGCCU G AGCAGCCA 966 UGGCUGCU UGAUG GCAUGCACUAUGC GCG AGGCCACC2741 69 CAGCCAAC G CAGCCGCA 967 UGCGGCUG UGAUG GCAUGCACUAUGC GCGGUUGGCUG 2742 75 ACGCAGCC G CAGGAGCC 968 GGCUCCUG UGAUG GCAUGCACUAUGCGCG GGCUGCGU 2743 94 GAGCCCUU G CCCCUGCC 969 GGCAGGGG UGAUGGCAUGCACUAUGC GCG AAGGGCUC 2744 100 UUGCCCCU G CCCGCGCC 970 GGCGCGGGUGAUG GCAUGCACUAUGC GCG AGGGGCAA 2745 104 CCCUGCCC G CGCCGCCG 971CGGCGGCG UGAUG GCAUGCACUAUGC GCG GGGCAGGG 2746 106 CUGCCCGC G CCGCCGCC972 GGCGGCGG UGAUG GCAUGCACUAUGC GCG GCGGGCAG 2747 109 CCCGCGCC GCCGCCCGC 973 GCGGGCGG UGAUG GCAUGCACUAUGC GCG GGCGCGGG 2748 112 GCGCCGCCG CCCGCCGG 974 CCGGCGGG UGAUG GCAUGCACUAUGC GCG GGCGGCGC 2749 116CGCCGCCC G CCGGGGGG 975 CCCCCCGG UGAUG GCAUGCACUAUGC GCG GGGCGGCG 2750137 GGGAAGCC G CCACCGGC 976 GCCGGUGG UGAUG GCAUGCACUAUGC GCG GGCUUCCC2751 148 ACCGGCCC G CCAUGCCC 977 GGGCAUGG UGAUG GCAUGCACUAUGC GCGGGGCCGGU 2752 153 CCCGCCAU G CCCGCCCC 978 GGGGCGGG UGAUG GCAUGCACUAUGCGCG AUGGCGGG 2753 157 CCAUGCCC G CCCCUCCC 979 GGGAGGGG UGAUGGCAUGCACUAUGC GCG GGGCAUGG 2754 172 CCAGCCCC G CCGGGAGC 980 GCUCCCGGUGAUG GCAUCCACUAUGC GCG GGGGCUGG 2755 183 GGGAGCCC G CGCCCGCU 981AGCGGGCG UGAUG GCAUGCACUAUGC GCG GGGCUCCC 2756 185 GAGCCCGC G CCCGCUGC982 GCAGCGGG UGAUG GCAUGCACUAUGC GCG GCGGGCUC 2757 189 CCGCGCCC GCUGCCCAG 983 CUGGGCAG UGAUG GCAUGCACUAUGC GCG GGGCGCGG 2758 192 CGCCCGCUG CCCAGGCU 984 AGCCUGGG UGAUG GCAUGCACUAUGC GCG AGCGGGCG 2759 205GGCUGGCC G CCGCCGUG 985 CACGGCGG UGAUG GCAUGCACUAUGC GCG GGCCAGCC 2760208 UGGCCGCC G CCGUGCCG 986 CGGCACGG UGAUG GCAUGCACUAUGC GCG GGCGGCCA2761 213 GCCGCCGU G CCGAUGUA 987 UACAUCGG UGAUG GCAUGCACUAUGC GCGACGGCGGC 2762 216 GCCGUGCC G AUGUAGCG 988 CGCUACAU UGAUG GCAUGCACUAUGCGCG GGCACGGC 2763 250 UCUCCCCU G CUCCCGUG 989 CACGGGAG UGAUGGCAUGCACUAUGC GCG AGGGGAGA 2764 258 GCUCCCGU G CUCUGCGG 990 CCGCAGAGUGAUG GCAUGCACUAUGC GCG ACGGGAGC 2765 263 CGUGCUCU G CGGAUCUC 991GAGAUCCG UGAUG GCAUGCACUAUGC GCG AGAGCACG 2766 276 UCUCCCCU G ACCGCUCU992 AGAGCGGU UGAUG GCAUGCACUAUGC GCG AGGGGAGA 2767 280 CCCUGACC GCUCUCCAC 993 GUGGAGAG UGAUG GCAUGCACUAUGC GCG GGUCAGGG 2768 320 AGGGCCCUG CAGGCCCU 994 AGGGCCUG UGAUG GCAUGCACUAUGC GCG AGGGCCCU 2769 337GGCGUCCU G AUGCCCCC 995 GGGGGCAU UGAUG GCAUGCACUAUGC GCG AGGACGCC 2770340 GUCCUGAU G CCCCCAAG 996 CUUGGGGG UGAUG GCAUGCACUAUGC GCG AUCAGGAC2771 360 CCUCUCCU G AGAAGCCA 997 UGGCUUCU UGAUG GCAUGCACUAUGC GCGAGGAGAGG 2772 397 GGGCAGGC G CCAGGGAC 998 GUCCCUGG UGAUG GCAUGCACUAUGCGCG GCCUGCCC 2773 420 GGGCCAGU G CGAGCCCA 999 UGGGCUCG UGAUGGCAUGCACUAUGC GCG ACUGGCCC 2774 422 GCCAGUGC G AGCCCAGA 1000 UCUGGGCUUGAUG GCAUGCACUAUGC GCG GCACUGGC 2775 437 GAGGGCCC G AAGGCCGG 1001CCGGCCUU UGAUG GCAUGCACUAUGC GCG GGGCCCUC 2776 468 CAAGCCCU G CCCUGGCU1002 AGCCAGGG UGAUG GCAUGCACUAUGC GCG AGGGCUUG 2777 480 UGGCUCCU GCUGUGGAU 1003 AUCCACAG UGAUG GCAUGCACUAUGC GCG AGGAGCCA 2778 493GGAUGGGC G CGGGAGUG 1004 CACUCCCG UGAUG GCAUGCACUAUGC GCG GCCCAUCC 2779501 GCGGGAGU G CUGCCUGC 1005 GCAGGCAG UGAUG GCAUGCACUAUGC GCG ACUCCCGC2780 504 GGAGUGCU G CCUGCCCA 1006 UGGGCAGG UGAUG GCAUGCACUAUGC GCGAGCACUCC 2781 508 UGCUGCCU G CCCACGGC 1007 GCCGUGGG UGAUG GCAUGCACUAUGCGCG AGGCAGCA 2782 537 AUCCGGCU G CCCCUGCG 1008 CGCAGGGG UGAUGGCAUGCACUAUGC GCG AGCCGGAU 2783 543 CUGCCCCU G CGCAGCGG 1009 CCGCUGCGUGAUG GCAUGCACUAUGC GCG AGGGGCAG 2784 545 GCCCCUGC G CAGCGGCC 1010GGCCGCUG UGAUG GCAUGCACUAUGC GCG GCAGGGGC 2785 562 UGGGGGGC G CCCCCCUG1011 CAGGGGGG UGAUG GCAUGCACUAUGC GCG GCCCCCCA 2786 576 CUGGGGCU GCGGCUGCC 1012 GGCAGCCG UGAUG GCAUGCACUAUGC GCG AGCCCCAG 2787 582CUGCGGCU G CCCCGGGA 1013 UCCCGGGG UGAUG GCAUGCACUAUGC GCG AGCCGCAG 2788595 GGGAGACC G ACGAAGAG 1014 CUCUUCGU UGAUG GCAUGCACUAUGC GCG GGUCUCCC2789 598 AGACCGAC G AAGAGCCC 1015 GGGCUCUU UGAUG GCAUGCACUAUGC GCGGUCGGUCU 2790 607 AAGAGCCC G AGGAGCCC 1016 GGGCUCCU UGAUG GCAUGCACUAUGCGCG GGGCUCUU 2791 654 GACAACCU G AGGGGCAA 1017 UUGCCCCU UGAUGGCAUGCACUAUGC GCG AGGUUGUC 2792 690 GUGGAGAU G ACCGUGGG 1018 CCCACGGUUGAUG GCAUGCACUAUGC GCG AUCUCCAC 2793 708 AGCCCCCC G CAGACGCU 1019AGCGUCUG UGAUG GCAUGCACUAUGC GCG GGGGGGCU 2794 714 CCGCAGAC G CUCAACAU1020 AUGUUGAG UGAUG GCAUGCACUAUGC GCG GUCUGCGG 2795 751 GUAACUUU GCAGUGGGU 1021 ACCCACUG UGAUG GCAUGCACUAUGC GCG AAAGUUAC 2796 760CAGUGGGU G CUGCCCCC 1022 GGGGGCAG UGAUG GCAUGCACUAUGC GCG ACCCACUG 2797763 UGGGUGCU G CCCCCCAC 1023 GUGGGGGG UGAUG GCAUGCACUAUGC GCG AGCACCCA2798 780 CCCUUCCU G CAUCGCUA 1024 UAGCGAUG UGAUG GCAUGCACUAUGC GCGAGGAAGGG 2799 785 CCUGCAUC G CUACUACC 1025 GGUAGUAG UGAUG GCAUGCACUAUGCGCG GAUGCAGG 2800 843 GUGUAUGU G CCCUACAC 1026 GUGUAGGG UGAUGGCAUGCACUAUGC GCG ACAUACAC 2801 883 UGGGCACC G ACCUGGUA 1027 UACCAGGUUGAUG GCAUGCACUAUGC GCG GGUGCCCA 2802 921 GUCACUGU G CGUGCCAA 1028UUGGCACG UGAUG GCAUGCACUAUGC GCG ACAGUGAC 2803 925 CUGUGCGU G CCAACAUU1029 AAUGUUGG UGAUG GCAUGCACUAUGC GCG ACGCACAG 2804 934 CCAACAUU GCUGCCAUC 1030 GAUGGCAG UGAUG GCAUGCACUAUGC GCG AAUGUUGG 2805 937ACAUUGCU G CCAUCACU 1031 AGUGAUGG UGAUG GCAUGCACUAUGC GCG AGCAAUGU 2806946 CCAUCACU G AAUCAGAC 1032 GUCUGAUU UGAUG GCAUGCACUAUGC GCG AGUGAUGG2807 1006 UGGCCUAU G CUGAGAUU 1033 AAUCUCAG UGAUG GCAUGCACUAUGC GCGAUAGGCCA 2808 1009 CCUAUGCU G AGAUUGCC 1034 GGCAAUCU UGAUG GCAUGCACUAUGCGCG AGCAUAGG 2809 1015 CUGAGAUU G CCAGGCCU 1035 AGGCCUGG UGAUGGCAUGCACUAUGC GCG AAUCUCAG 2810 1024 CCAGGCCU G ACGACUCC 1036 GGAGUCGUUGAUG GCAUGCACUAUGC GCG AGGCCUGG 2811 1027 GGCCUGAC G ACUCCCUG 1037CAGGGAGU UGAUG GCAUGCACUAUGC GCG GUCAGGCC 2812 1048 CUUUCUUU G ACUCUCUG1038 CAGAGAGU UGAUG GCAUGCACUAUGC GCG AAAGAAAG 2813 1092 UUCUCCCU GCAGCUUUG 1039 CAAAGCUG UGAUG GCAUGCACUAUGC GCG AGGGAGAA 2814 1105UUUGUGGU G CUGGCUUC 1040 GAAGCCAG UGAUG GCAUGCACUAUGC GCG ACCACAAA 28151129 ACCAGUCU G AAGUGCUG 1041 CAGCACUU UGAUG GCAUGCACUAUGC GCG AGACUGGU2816 1134 UCUGAAGU G CUGGCCUC 1042 GAGGCCAG UGAUG GCAUGCACUAUGC GCGACUUCAGA 2817 1158 GGGAGCAU G AUCAUUGG 1043 CCAAUGAU UGAUG GCAUGCACUAUGCGCG AUGCUCCC 2818 1174 GAGGUAUC G ACCACUCG 1044 CGAGUGGU UGAUGGCAUGCACUAUGC GCG GAUACCUC 2819 1182 GACCACUC G CUGUACAC 1045 GUGUACAGUGAUG GCAUGCACUAUGC GCG GAGUGGUC 2820 1234 GGUAUUAU G AGGUGAUC 1046GAUCACCU UGAUG GCAUGCACUAUGC GCG AUAAUACC 2821 1239 UAUGAGGU G AUCAUUGU1047 ACAAUGAU UGAUG GCAUGCACUAUGC GCG ACCUCAUA 2822 1248 AUCAUUGU GCGGGUGGA 1048 UCCACCCG UGAUG GCAUGCACUAUGC GCG ACAAUGAU 2823 1275CAGGAUCU G AAAAUGGA 1049 UCCAUUUU UGAUG GCAUGCACUAUGC GCG AGAUCCUG 28241286 AAUGGACU G CAAGGAGU 1050 ACUCCUUG UGAUG GCAUGCACUAUGC GCG AGUCCAUU2825 1303 ACAACUAU G ACAAGAGC 1051 GCUCUUGU UGAUG GCAUGCACUAUGC GCGAUAGUUGU 2826 1344 CUUCGUUU G CCCAAGAA 1052 UUCUUGGG UGAUG GCAUGCACUAUGCGCG AAACGAAG 2827 1360 AAGUGUUU G AAGCUGCA 1053 UGCAGCUU UGAUGGCAUGCACUAUGC GCG AAACACUU 2828 1366 UUGAAGCU G CAGUCAAA 1054 UUUGACUGUGAUG GCAUGCACUAUGC GCG AGCUUCAA 2829 1411 AGUUCCCU G AUGGUUUC 1055GAAACCAU UGAUG GCAUGCACUAUGC GCG AGGGAACU 2830 1442 GCUGGUGU G CUGGCAAG1056 CUUGCCAG UGAUG GCAUGCACUAUGC GCG ACACCAGC 2831 1504 UAAUGGGU GAGGUUACC 1057 GGUAACCU UGAUG GCAUGCACUAUGC GCG ACCCAUUA 2832 1526GUCCUUCC G CAUCACCA 1058 UGGUGAUG UGAUG GCAUGCACUAUGC GCG GGAAGGAC 28331542 AUCCUUCC G CAGCAAUA 1059 UAUUGCUG UGAUG GCAUGCACUAUGC GCG GGAAGGAU2834 1554 CAAUACCU G CGGCCAGU 1060 ACUGGCCG UGAUG GCAUGCACUAUGC GCGAGGUAUUG 2835 1588 CCCAAGAC G ACUGUUAC 1061 GUAACAGU UGAUG GCAUGCACUAUGCGCG GUCUUGGG 2836 1603 ACAAGUUU G CCAUCUCA 1062 UGAGAUGG UGAUGGCAUGCACUAUGC GCG AAACUUGU 2837 1672 UUGUCUUU G AUCGGGCC 1063 GGCCCGAUUGAUG GCAUGCACUAUGC GCG AAAGACAA 2838 1682 UCGGGCCC G AAAACGAA 1064UUCGUUUU UGAUG GCAUGCACUAUGC GCG GGGCCCGA 2839 1688 CCGAAAAC G AAUUGGCU1065 AGCCAAUU UGAUG GCAUGCACUAUGC GCG GUUUUCGG 2840 1699 UUGGCUUU GCUGUCAGC 1066 GCUGACAG UGAUG GCAUGCACUAUGC GCG AAAGCCAA 2841 1708CUGUCAGC G CUUGCCAU 1067 AUGGCAAG UGAUG GCAUGCACUAUGC GCG GCUGACAG 28421712 CAGCGCUU G CCAUGUGC 1068 GCACAUGG UGAUG GCAUGCACUAUGC GCG AAGCGCUG2843 1719 UGCCAUGU G CACGAUGA 1069 UCAUCGUG UGAUG GCAUGCACUAUGC GCGACAUGGCA 2844 1723 AUGUGCAC G AUGAGUUC 1070 GAACUCAU UGAUG GCAUGCACUAUGCGCG GUGCACAU 2845 1726 UGCACGAU G AGUUCAGG 1071 CCUGAACU UGAUGGCAUGCACUAUGC GCG AUCGUGCA 2846 1807 AGACAGAU G AGUCAACC 1072 GGUUGACUUGAUG GCAUGCACUAUGC GCG AUCUGUCU 2847 1821 ACCCUCAU G ACCAUAGC 1073GCUAUGGU UGAUG GCAUGCACUAUGC GCG AUGAGGGU 2848 1843 UCAUGGCU G CCAUCUGC1074 GCAGAUGG UGAUG GCAUGCACUAUGC GCG AGCCAUGA 2849 1850 UGCCAUCU GCGCCCUCU 1075 AGAGGGCG UGAUG GCAUGCACUAUGC GCG AGAUGGCA 2850 1852CCAUCUGC G CCCUCUUC 1076 GAAGAGGG UGAUG GCAUGCACUAUGC GCG GCAGAUGG 28511863 CUCUUCAU G CUGCCACU 1077 AGUGGCAG UGAUG GCAUGCACUAUGC GCG AUGAAGAG2852 1866 UUCAUGCU G CCACUCUG 1078 CAGAGUGG UGAUG GCAUGCACUAUGC GCGAGCAUGAA 2853 1874 GCCACUCU G CCUCAUGG 1079 CCAUGAGG UGAUG GCAUGCACUAUGCGCG AGAGUGGC 2854 1895 UCAGUGGC G CUGCCUCC 1080 GGAGGCAG UGAUGGCAUGCACUAUGC GCG GCCACUGA 2855 1898 GUGGCGCU G CCUCCGCU 1081 AGCGGAGGUGAUG GCAUGCACUAUGC GCG AGCGCCAC 2856 1904 CUGCCUCC G CUGCCUGC 1082GCAGGCAG UGAUG GCAUGCACUAUGC GCG GGAGGCAG 2857 1907 CCUCCGCU G CCUGCGCC1083 GGCGCAGG UGAUG GCAUGCACUAUGC GCG AGCGGAGG 2858 1911 CGCUGCCU GCGCCAGCA 1084 UGCUGGCG UGAUG GCAUGCACUAUGC GCG AGGCAGCG 2859 1913CUGCCUGC G CCAGCAGC 1085 GCUGCUGG UGAUG GCAUGCACUAUGC GCG GCAGGCAG 28601924 AGCAGCAU G AUGACUUU 1086 AAAGUCAU UGAUG GCAUGCACUAUGC GCG AUGCUGCU2861 1927 AGCAUGAU G ACUUUGCU 1087 AGCAAACU UGAUG GCAUGCACUAUGC GCGAUCAUGCU 2862 1933 AUGACUUU G CUGAUGAC 1088 GUCAUCAG UGAUG GCAUGCACUAUGCGCG AAAGUCAU 2863 1936 ACUUUGCU G AUGACAUC 1089 GAUGUCAU UGAUGGCAUGCACUAUGC GCG AGCAAAGU 2864 1939 UUGCUGAU G ACAUCUCC 1090 GGAGAUGUUGAUG GCAUGCACUAUGC GCG AUCAGCAA 2865 1950 AUCUCCCU G CUGAAGUG 1091CACUUCAG UGAUG GCAUGCACUAUGC GCG AGGGAGAU 2866 1953 UCCCUGCU G AAGUGAGG1092 CCUCACUU UGAUG GCAUGCACUAUGC GCG AGCAGGGA 2867 1958 GCUGAAGU GAGGAGGCC 1093 GGCCUCCU UGAUG GCAUGCACUAUGC GCG ACUUCAGC 2868 2087CACCAAAU G CCUCUGCC 1094 GGCAGAGG UGAUG GCAUGCACUAUGC GCG AUUUGGUG 28692093 AUGCCUCU G CCUUGAUG 1095 CAUCAAGG UGAUG GCAUGCACUAUGC GCG AGAGGCAU2870 2098 UCUGCCUU G AUGGAGAA 1096 UUCUCCAU UGAUG GCAUGCACUAUGC GCGAAGGCAGA 2871 2179 AGCACUCU G CUGGCGGG 1097 CCCGCCAG UGAUG GCAUGCACUAUGCGCG AGAGUGCU 2872 2227 GAAAUUCU G CUGCUUGA 1098 UCAAGCAG UGAUGGCAUGCACUAUGC GCG AGAAUUUC 2873 2230 AUUCUGCU G CUUGAAAC 1099 GUUUCAAGUGAUG GCAUGCACUAUGC GCG AGCAGAAU 2874 2234 UGCUGCUU G AAACUUCA 1100UGAAGUUU UGAUG GCAUGCACUAUGC GCG AAGCAGCA 2875 2248 UCAGCCCU G AACCUUUG1101 CAAAGGUU UGAUG GCAUGCACUAUGC GCG AGGGCUGA 2876 2329 CAUCACAC GCAGGUUAC 1102 GUAACCUG UGAUG GCAUGCACUAUGC GCG GUGUGAUG 2877 2393GUUUCCCU G CUGGCCAA 1103 UUGGCCAG UGAUG GCAUGCACUAUGC GCG AGGGAAAC 28782419 GAGAGGAU G CACAGUUU 1104 AAACUGUG UGAUG GCAUGCACUAUGC GCG AUCCUCUC2879 2428 CACAGUUU G CUAUUUGC 1105 GCAAAUAG UGAUG GCAUGCACUAUGC GCGAAACUGUG 2880 2435 UGCUAUUU G CUUUAGAG 1106 CUCUAAAG UGAUG GCAUGCACUAUGCGCG AAAUAGCA 2881 2476 ACAUUGGU G CAAAGAUU 1107 AAUCUUUG UGAUGGCAUGCACUAUGC GCG ACCAAUGU 2882 2485 CAAAGAUU G CCUCUUGA 1108 UCAAGAGGUGAUG GCAUGCACUAUGC GCG AAUCUUUG 2883 2492 UGCCUCUU G AAUUAAAA 1109UUUUAAUU UGAUG GCAUGCACUAUGC GCG AAGAGGCA 2884 219 GUGCCGAU G UAGCGGGC1110 GCCCGCUA UGAUG GCAUGCACUAUGC GCG AUCGGCAC 2885 483 CUCCUGCU GUGGAUGGG 1111 CCCAUCCA UGAUG GCAUGCACUAUGC GCG AGCAGGAG 2886 634GCAGCUUU G UGGAGAUG 1112 CAUCUCCA UGAUG GCAUGCACUAUGC GCG AAAGCUGC 2887804 AGGCAGCU G UCCAGCAC 1113 GUGCUGGA UGAUG GCAUGCACUAUGC GCG AGCUGCCU2888 835 GGAAGGGU G UGUAUGUG 1114 CACAUACA UGAUG GCAUGCACUAUGC GCGACCCUUCC 2889 837 AAGGGUGU G UAUGUGCC 1115 GGCACAUA UGAUG GCAUGCACUAUGCGCG ACACCCUU 2890 841 GUGUGUAU G UGCCCUAC 1116 GUAGGGCA UGAUGGCAUGCACUAUGC GCG AUACACAC 2891 919 ACGUCACU G UGCGUGCC 1117 GGCACGCAUGAUG GCAUGCACUAUGC GCG AGUGACGU 2892 1100 GCAGCUUU G UGGUGCUG 1118CAGCACCA UGAUG GCAUGCACUAUGC GCG AAAGCUGC 2893 1144 UGGCCUCU G UCGGAGGG1119 CCCUCCGA UGAUG GCAUGCACUAUGC GCG AGAGGCCA 2894 1185 CACUCGCU GUACACAGG 1120 CCUGUGUA UGAUG GCAUGCACUAUGC GCG AGCGAGUG 2895 1246UGAUCAUU G UGCGGGUG 1121 CACCCGCA UGAUG GCAUGCACUAUGC GCG AAUGAUCA 28961315 AGAGCAUU G UCGACAGU 1122 ACUGUCCA UGAUG GCAUGCACUAUGC GCG AAUGCUCU2897 1356 AAGAAAGU G UUUGAAGC 1123 GCUUCAAA UGAUG GCAUGCACUAUGC GCGACUUUCUU 2898 1440 CAGCUGGU G UGCUGGCA 1124 UGCCAGCA UGAUG GCAUGCACUAUGCGCG ACCAGCUG 2899 1570 UGGAAGAU G UGGCCACG 1125 CGUGGCCA UGAUGGCAUGCACUAUGC GCG AUCUUCCA 2900 1592 AGACGACU G UUACAAGU 1126 ACUUGUAAUGAUG GCAUGCACUAUGC GCG AGUCGUCU 2901 1630 CGGGCACU G UUAUGGGA 1127UCCCAUAA UGAUG GCAUGCACUAUGC GCG AGUGCCCG 2902 1642 UGGGAGCU G UUAUCAUG1128 CAUGAUAA UGAUG GCAUGCACUAUGC GCG AGCUCCCA 2903 1666 UCUACGUU GUCUUUGAU 1129 AUCAAAGA UGAUG GCAUGCACUAUGC GCG AACGUAGA 2904 1702GCUUUGCU G UCAGCGCU 1130 AGCGCUGA UGAUG GCAUGCACUAUGC GCG AGCAAAGC 29051717 CUUGCCAU G UGCACGAU 1131 AUCGUGCA UGAUG GCAUGCACUAUGC GCG AUGGCAAG2906 1759 GCCCUUUU G UCACCUUG 1132 CAAGGUGA UGAUG GCAUGCACUAUGC GCGAAAAGGGC 2907 1781 GGAAGACU G UGGCUACA 1133 UGUAGCCA UGAUG GCAUGCACUAUGCGCG AGUCUUCC 2908 1834 UAGCCUAU G UCAUGGCU 1134 AGCCAUGA UGAUGGCAUGCACUAUGC GCG AUAGGCUA 2909 1884 CUCAUGGU G UGUCAGUG 1135 CACUGACAUGAUG GCAUGCACUAUGC GCG ACCAUGAG 2910 1886 CAUGGUGU G UCAGUGGC 1136GCCACUGA UGAUG GCAUGCACUAUGC GCG ACACCAUG 2911 2048 UGGCACCU G UGGCCAGA1137 UCUGGCCA UGAUG GCAUGCACUAUGC GCG AGGUGCCA 2912 2139 CAGGGACU GUACCUGUA 1138 UACAGGUA UGAUG GCAUGCACUAUGC GCG AGUCCCUG 2913 2145CUGUACCU G UAGGAAAC 1139 GUUUCCUA UGAUG GCAUGCACUAUGC GCG AGGUACAG 29142256 GAACCUUU G UCCACCAU 1140 AUGGUGGA UGAUG GCAUGCACUAUGC GCG AAAGGUUC2915 2346 CUUGGCGU G UGUCCCUG 1141 CAGGGACA UGAUG GCAUGCACUAUGC GCGACGCCAAG 2916 2348 UGGCGUGU G UCCCUGUG 1142 CACAGGGA UGAUG GCAUGCACUAUGCGCG ACACGCCA 2917 2354 GUGUCCCU G UGGUACCC 1143 GGGUACCA UGAUGGCAUGCACUAUGC GCG AGGGACAC 2918 2385 CCAAGCUU G UUUCCCUG 1144 CAGGGAAAUGAUG GCAUGCACUAUGC GCG AAGCUUGG 2919 2453 CAGGGACU G UAUAAACA 1145UGUUUAUA UGAUG GCAUGCACUAUGC GCG AGUCCCUG 2920

[0307] TABLE VI Human BACE Zinzyme Ribozyme and Target Sequence PosSubstrate Seq ID Zinzyme Seq ID 11 ACGCGUCC G CAGCCCGC 960 GCGGGCUGGCCGAAAGGCGAGUCAAGGUCU GGACGCGU 2921 18 CGCAGCCC G CCCGGGAG 961 CUCCCGGGGCCGAAAGGCGAGUCAAGGUCU GGGCUGCG 2922 29 CGGGAGCU G CGAGCCGC 962 GCGGCUCGGCCGAAAGGCGAGUCAAGGUCU AGCUCCCG 2923 36 UGCGAGCC G CGAGCUGG 964 CCAGCUCGGCCGAAAGGCGAGUCAAGGUCU GGCUCGCA 2924 69 CAGCCAAC G CAGCCGCA 967 UGCGGCUGGCCGAAAGGCGAGUCAAGGUCU GUUGGCUG 2925 75 ACGCAGCC G CAGGAGCC 968 GGCUCCUGGCCGAAAGGCGAGUCAAGGUCU GGCUGCGU 2926 94 GAGCCCUU G CCCCUGCC 969 GGCAGGGGGCCGAAAGGCGAGUCAAGGUCU AAGGGCUC 2927 100 UUGCCCCU G CCCGCGCC 970GGCGCGGG GCCGAAAGGCGAGUCAAGGUCU AGGGGCAA 2928 104 CCCUGCCC G CGCCGCCG971 CGGCGGCG GCCGAAAGGCGAGUCAAGGUCU GGGCAGGG 2929 106 CUGCCCGC GCCGCCGCC 972 GGCGGCGG GCCGAAAGGCGAGUCAAGGUCU GCGGGCAG 2930 109 CCCGCGCCG CCGCCCGC 973 GCGGGCGG GCCGAAAGGCGAGUCAAGGUCU GGCGCGGG 2931 112GCGCCGCC G CCCGCCGG 974 CCGGCGGG GCCGAAAGGCGAGUCAAGGUCU GGCGGCGC 2932116 CGCCGCCC G CCGGGGGG 975 CCCCCCGG GCCGAAAGGCGAGUCAAGGUCU GGGCGGCG2933 137 GGGAAGCC G CCACCGGC 976 GCCGGUGG GCCGAAAGGCGAGUCAAGGUCUGGCUUCCC 2934 148 ACCGGCCC G CCAUGCCC 977 GGGCAUGGGCCGAAAGGCGAGUCAAGGUCU GGGCCGGU 2935 153 CCCGCCAU G CCCGCCCC 978GGGGCGGG GCCGAAAGGCGAGUCAAGGUCU AUGGCGGG 2936 157 CCAUGCCC G CCCCUCCC979 GGGAGGGG GCCGAAAGGCGAGUCAAGGUCU GGGCAUGG 2937 172 CCAGCCCC GCCGGGAGC 980 GCUCCCGG GCCGAAAGGCGAGUCAAGGUCU GGGGCUGC 2938 183 GGGAGCCCG CGCCCGCU 981 AGCGGGCG GCCGAAAGGCGAGUCAAGGUCU GGGCUCCC 2939 185GAGCCCGC G CCCGCUGC 982 GCAGCGGG GCCGAAAGGCGAGUCAAGGUCU GCGGGCUC 2940189 CCGCGCCC G CUGCCCAG 983 CUGGGCAG GCCGAAAGGCGAGUCAAGGUCU GGGCGCGG2941 192 CGCCCGCU G CCCAGGCU 984 AGCCUGGG GCCGAAAGGCGAGUCAAGGUCUAGCGGGCG 2942 205 GGCUGGCC G CCGCCGUG 985 CACGGCGGGCCGAAAGGCGAGUCAAGGUCU GGCCAGCC 2943 208 UGGCCGCC G CCGUGCCG 986CGGCACGG GCCGAAAGGCGAGUCAAGGUCU GGCGGCCA 2944 213 GCCGCCGU G CCGAUGUA987 UACAUCGG GCCGAAAGGCGAGUCAAGGUCU ACGGCGGC 2945 250 UCUCCCCU GCUCCCGUG 989 CACGGGAG GCCGAAAGGCGAGUCAAGGUCU AGGGGAGA 2946 258 GCUCCCGUG CUCUGCGG 990 CCGCAGAG GCCCAAAGGCGAGUCAAGGUCU ACGGGAGC 2947 263CGUGCUCU G CGGAUCUC 991 GAGAUCCG GCCGAAAGGCGAGUCAAGGUCU AGAGCACG 2948280 CCCUGACC G CUCUCCAC 993 GUGGAGAG GCCGAAAGGCGAGUCAAGGUCU GGUCAGGG2949 320 AGGGCCCU G CAGGCCCU 994 AGGGCCUG GCCGAAAGGCGAGUCAAGGUCUAGGGCCCU 2950 340 GUCCUGAU G CCCCCAAG 996 CUUGGGGGGCCGAAAGGCGAGUCAAGGUCU AUCAGGAC 2951 397 GGGCAGGC G CCAGGGAG 998GUCCCUGG GCCGAAAGGCGAGUCAAGGUCU GCCUGCCC 2952 420 GGGCCAGU G CGAGCCCA999 UGGGCUCG GCCGAAAGGCGAGUCAAGGUCU ACUGGCCC 2953 468 CAAGCCCU GCCCUGGCU 1002 AGCCAGGG GCCGAAAGGCGAGUCAAGGUCU AGGGCUUG 2954 480 UGGCUCCUG CUGUGGAU 1003 AUCCACAG GCCGAAAGGCGAGUCAAGGUCU AGGAGCCA 2955 493GGAUGGGC G CGGGAGUG 1004 CACUCCCG GCCGAAAGGCGAGUCAAGGUCU GCCCAUCC 2956501 GCGGGAGU G CUGCCUGC 1005 GCAGGCAG GCCGAAAGGCGAGUCAAGGUCU ACUCCCGC2957 504 GGAGUGCU G CCUGCCCA 1006 UGGGCAGG GCCGAAAGGCGAGUCAAGGUCUAGCACUCC 2958 508 UGCUGCCU G CCCACGGC 1007 GCCGUGGGGCCGAAAGGCGAGUCAAGGUCU AGGCAGCA 2959 537 AUCCGGCU G CCCCUGCG 1008CGCAGGGG GCCGAAAGGCGAGUCAAGGUCU AGCCGGAU 2960 543 CUGCCCCU G CGCAGCGG1009 CCGCUGCG GCCGAAAGGCGAGUCAAGGUCU AGGGGCAG 2961 545 GCCCCUGC GCAGCGGCC 1010 GGCCGCUG GCCGAAAGGCGAGUCAAGGUCU GCAGCGGC 2962 562 UGGGGGGCG CCCCCCUG 1011 CAGGGGGG GCCGAAAGGCGAGUCAAGGUCU GCCCCCCA 2963 576CUGGGGCU G CGGCUGCC 1012 GGCAGCCG GCCGAAAGGCGAGUCAAGGUCU AGCCCCAG 2964582 CUGCGGCU G CCCCGGGA 1013 UCCCGGGG GCCGAAAGGCGAGUCAAGGUCU AGCCGCAG2965 708 AGCCCCCC G CAGACGCU 1019 AGCGUCUG GCCGAAAGGCGAGUCAAGGUCUGGGGGGCU 2966 714 CCGCAGAC G CUCAACAU 1020 AUGUUGAGGCCGAAAGGCGAGUCAAGGUCU GUCUGCGG 2967 751 GUAACUUU G CAGUGGGU 1021ACCCACUG GCCGAAAGGCGAGUCAAGGUCU AAAGUUAC 2968 760 CAGUGGGU G CUGCCCCC1022 GGGGGCAG GCCGAAAGGCGAGUCAAGGUCU ACCCACUG 2969 763 UGGGUGCU GCCCCCCAC 1023 GUGGGGGG GCCGAAAGGCGAGUCAAGGUCU AGCACCCA 2970 780 CCCUUCCUG CAUCGCUA 1024 UAGCGAUG GCCGAAAGGCGAGUCAAGGUCU AGGAAGGG 2971 785CCUGCAUC G CUACUACC 1025 GGUAGUAG GCCGAAAGGCGAGUCAAGGUCU GAUGCAGG 2972843 GUGUAUGU G CCCUACAC 1026 GUGUAGGG GCCGAAAGGCGAGUCAAGGUCU ACAUACAC2973 921 GUCACUGU G CGUGCCAA 1028 UUGGCACG GCCGAAAGGCGAGUCAAGGUCUACAGUGAC 2974 925 CUGUGCGU G CCAACAUU 1029 AAUGUUGGGCCGAAAGGCGAGUCAAGGUCU ACGCACAG 2975 934 CCAACAUU G CUGCCAUC 1030GAUGGCAG GCCGAAAGGCGAGUCAAGGUCU AAUGUUGG 2976 937 ACAUUGCU G CCAUCACU1031 AGUGAUGG GCCGAAAGGCGAGUCAAGGUCU AGCAAUGU 2977 1006 UGGCCUAU GCUGAGAUU 1033 AAUCUCAG GCCGAAAGGCGAGUCAAGGUCU AUAGGCCA 2978 1015CUGAGAUU G CCAGGCCU 1035 AGGCCUGG GCCGAAAGGCGAGUCAAGGUCU AAUCUCAG 29791092 UUCUCCCU G CAGCUUUG 1039 CAAAGCUG GCCGAAAGGCGAGUCAAGGUCU AGGGAGAA2980 1105 UUUGUGGU G CUGGCUUC 1040 GAAGCCAG GCCGAAAGGCGAGUCAAGGUCUACCACAAA 2981 1134 UCUGAAGU G CUGGCCUC 1042 GAGGCCAGGCCGAAAGGCGAGUCAAGGUCU ACUUCAGA 2982 1182 GACCACUC G CUGUACAC 1045GUGUACAG GCCGAAAGGCGAGUCAAGGUCU GAGUGGUC 2983 1248 AUCAUUGU G CGGGUGGA1048 UCCACCCG GCCGAAAGGCGAGUCAAGGUCU ACAAUGAU 2984 1286 AAUGGACU GCAAGGAGU 1050 ACUCCUUG GCCGAAAGGCGAGUCAAGGUCU AGUCCAUU 2985 1344CUUCGUUU G CCCAAGAA 1052 UUCUUGGG GCCGAAAGGCGAGUCAAGGUCU AAACGAAG 29861366 UUGAAGCU G CAGUCAAA 1054 UUUGACUG GCCGAAAGGCGAGUCAAGGUCU AGCUUCAA2987 1442 GCUGGUGU G CUGGCAAG 1056 CUUGCCAG GCCGAAAGGCGAGUCAAGGUCUACACCAGC 2988 1526 GUCCUUCC G CAUCACCA 1058 UGGUGAUGGCCGAAAGGCGAGUCAAGGUCU GGAAGGAC 2989 1542 AUCCUUCC G CAGCAAUA 1059UAUUGCUG GCCGAAAGGCGAGUCAAGGUCU GGAAGGAU 2990 1554 CAAUACCU G CGGCCAGU1060 ACUGGCCG GCCGAAAGGCGAGUCAAGGUCU AGGUAUUG 2991 1603 ACAAGUUU GCCAUCUCA 1062 UGAGAUGG GCCGAAAGGCGAGUCAAGGUCU AAACUUGU 2992 1699UUGGCUUU G CUGUCAGC 1066 GCUGACAG GCCGAAAGGCGAGUCAAGGUCU AAAGCCAA 29931708 CUGUCAGC G CUUGCCAU 1067 AUGGCAAG GCCGAAAGGCGAGUCAAGGUCU GCUGACAG2994 1712 CAGCGCUU G CCAUGUGC 1068 GCACAUGG GCCGAAAGGCGAGUCAAGGUCUAAGCGCUG 2995 1719 UGCCAUGU G CACGAUGA 1069 UCAUCGUGGCCGAAAGGCGAGUCAAGGUCU ACAUGGCA 2996 1843 UCAUGGCU G CCAUCUGC 1074GCAGAUGG GCCGAAAGGCGAGUCAAGGUCU AGCCAUGA 2997 1850 UGCCAUCU G CGCCCUCU1075 AGAGGGCG GCCGAAAGGCGAGUCAAGGUCU AGAUGGCA 2998 1852 CCAUCUGC GCCCUCUUC 1076 GAACAGGG GCCGAAAGGCGAGUCAAGGUCU GCAGAUGG 2999 1863CUCUUCAU G CUGCCACU 1077 AGUGGCAG GCCGAAAGGCGAGUCAAGGUCU AUGAAGAG 30001866 UUCAUGCU G CCACUCUG 1078 CAGAGUGG GCCGAAAGGCGAGUCAAGGUCU AGCAUGAA3001 1874 GCCACUCU G CCUCAUGG 1079 CCAUGAGG GCCGAAAGGCGAGUCAAGGUCUAGAGUGGC 3002 1895 UCAGUGGC G CUGCCUCC 1080 GGAGGCAGGCCGAAAGGCGAGUCAAGGUCU GCCACUGA 3003 1898 GUGGCGCU G CCUCCGCU 1081AGCGGAGG GCCGAAAGGCGAGUCAAGGUCU AGCGCCAC 3004 1904 CUGCCUCC G CUGCCUGC1082 GCAGGCAG GCCGAAAGGCGAGUCAAGGUCU GGAGGCAG 3005 1907 CCUCCGCU GCCUGCGCC 1083 GGCGCAGG GCCGAAAGGCGAGUCAAGGUCU AGCGGAGG 3006 1911CGCUGCCU G CGCCAGCA 1084 UGCUGGCG GCCGAAAGGCGAGUCAAGGUCU AGGCAGCG 30071913 CUGCCUGC G CCAGCAGC 1085 GCUGCUGG GCCGAAAGGCGAGUCAAGGUCU GCAGGCAG3008 1933 AUGACUUU G CUGAUGAC 1088 GUCAUCAG GCCGAAAGGCGAGUCAAGGUCUAAAGUCAU 3009 1950 AUCUCCCU G CUGAAGUG 1091 CACUUCAGGCCGAAAGGCGAGUCAAGGUCU AGGGAGAU 3010 2087 CACCAAAU G CCUCUGCC 1094GGCAGAGG GCCGAAAGGCGAGUCAAGGUCU AUUUGGUG 3011 2093 AUGCCUCU G CCUUGAUG1095 CAUCAAGG GCCGAAAGGCGAGUCAAGGUCU AGAGGCAU 3012 2179 AGCACUCU GCUGGCGGG 1097 CCCGCCAG GCCGAAAGGCGAGUCAAGGUCU AGAGUGCU 3013 2227GAAAUUCU G CUGCUUGA 1098 UCAAGCAG GCCGAAAGGCGAGUCAAGGUCU AGAAUUUC 30142230 AUUCUGCU G CUUGAAAC 1099 GUUUCAAG GCCGAAAGGCGAGUCAAGGUCU AGCAGAAU3015 2329 CAUCACAC G CAGGUUAC 1102 GUAACCUG GCCGAAAGGCGAGUCAAGGUCUGUGUGAUG 3016 2393 GUUUCCCU G CUGGCCAA 1103 UUGGCCAGGCCGAAAGGCGAGUCAAGGUCU AGGGAAAC 3017 2419 GAGAGGAU G CACAGUUU 1104AAACUGUG GCCGAAAGGCGAGUCAAGGUCU AUCCUCUC 3018 2428 CACAGUUU G CUAUUUGC1105 GCAAAUAG GCCGAAAGGCGAGUCAAGGUCU AAACUGUG 3019 2435 UGCUAUUU GCUUUAGAG 1106 CUCUAAAG GCCGAAAGGCGAGUCAAGGUCU AAAUAGCA 3020 2476ACAUUGGU G CAAAGAUU 1107 AAUCUUUG GCCGAAAGGCGAGUCAAGGUCU ACCAAUGU 30212485 CAAAGAUU G CCUCUUGA 1108 UCAAGAGG GCCGAAAGGCGAGUCAAGGUCU AAUCUUUG3022 219 GUGCCGAU G UAGCGGGC 1110 GCCCGCUA GCCGAAAGGCGAGUCAAGGUCUAUCGGCAC 3023 483 CUCCUGCU G UGGAUGGG 1111 CCCAUCCAGCCGAAAGGCGAGUCAAGGUCU AGCAGGAG 3024 634 GCAGCUUU G UGGAGAUG 1112CAUCUCCA GCCGAAAGGCGAGUCAAGGUCU AAAGCUGC 3025 804 AGGCAGCU G UCCAGCAC1113 GUGCUGGA GCCGAAAGGCGAGUCAAGGUCU AGCUGCCU 3026 835 GGAAGGGU GUGUAUGUG 1114 CACAUACA GCCGAAAGGCGAGUCAAGGUCU ACCCUUCC 3027 837 AAGGGUGUG UAUGUGCC 1115 GGCACAUA GCCGAAAGGCGAGUCAAGGUCU ACACCCUU 3028 841GUGUGUAU G UGCCCUAC 1116 GUAGGGCA GCCGAAAGGCGAGUCAAGGUCU AUACACAC 3029919 ACGUCACU G UGCGUGCC 1117 GGCACGCA GCCGAAAGGCGAGUCAAGGUCU AGUGACGU3030 1100 GCAGCUUU G UGGUGCUG 1118 CAGCACCA GCCGAAAGGCGAGUCAAGGUCUAAAGCUGC 3031 1144 UGGCCUCU G UCGGAGGG 1119 CCCUCCGAGCCGAAAGGCGAGUCAAGGUCU AGAGGCCA 3032 1185 CACUCGCU G UACACAGG 1120CCUGUGUA GCCGAAAGGCGAGUCAAGGUCU AGCGAGUG 3033 1246 UGAUCAUU G UGCGGGUG1121 CACCCGCA GCCGAAAGGCGAGUCAAGGUCU AAUGAUCA 3034 1315 AGAGCAUU GUGGACAGU 1122 ACUGUCCA GCCGAAAGGCGAGUCAAGGUCU AAUGCUCU 3035 1356AAGAAAGU G UUUGAAGC 1123 GCUUCAAA GCCGAAAGGCGAGUCAAGGUCU ACUUUCUU 30361440 CAGCUGGU G UGCUGGCA 1124 UGCCAGCA GCCGAAAGGCGAGUCAAGGUCU ACCAGCUG3037 1570 UGGAAGAU G UGGCCACG 1125 CGUGGCCA GCCGAAAGGCGAGUCAAGGUCUAUCUUCCA 3038 1592 AGACGACU G UUACAAGU 1126 ACUUGUAAGCCGAAAGGCGAGUCAAGGUCU AGUCGUCU 3039 1630 CGGGCACU G UUAUGGGA 1127UCCCAUAA GCCGAAAGGCGAGUCAAGGUCU AGUGCCCG 3040 1642 UGGGAGCU G UUAUCAUG1128 CAUGAUAA GCCGAAAGGCGAGUCAAGGUCU AGCUCCCA 3041 1666 UCUACGUU GUCUUUGAU 1129 AUCAAAGA GCCGAAAGGCGAGUCAAGGUCU AACGUAGA 3042 1702GCUUUGCU G UCAGCGCU 1130 AGCGCUGA GCCGAAAGGCGAGUCAAGGUCU AGCAAAGC 30431717 CUUGCCAU G UGCACGAU 1131 AUCGUGCA GCCGAAAGGCGAGUCAAGGUCU AUGGCAAG3044 1759 GCCCUUUU G UCACCUUG 1132 CAAGGUGA GCCGAAAGGCGAGUCAAGGUCUAAAAGGGC 3045 1781 GGAAGACU G UGGCUACA 1133 UGUAGCCAGCCGAAAGGCGAGUCAAGGUCU AGUCUUCC 3046 1834 UAGCCUAU G UCAUGGCU 1134AGCCAUGA GCCGAAAGGCGAGUCAAGGUCU AUAGGCUA 3047 1884 CUCAUGGU G UGUCAGUG1135 CACUGACA GCCGAAAGGCGAGUCAAGGUCU ACCAUGAG 3048 1886 CAUGGUGU GUCAGUGGC 1136 GCCACUGA GCCGAAAGGCGAGUCAAGGUCU ACACCAUG 3049 2048UGGCACCU G UGGCCAGA 1137 UCUGGCCA GCCGAAAGGCGAGUCAAGGUCU AGGUGCCA 30502139 CAGGGACU G UACCUGUA 1138 UACAGGUA GCCGAAAGGCGAGUCAAGGUCU AGUCCCUG3051 2145 CUGUACCU G UAGGAAAC 1139 GUUUCCUA GCCGAAAGGCGAGUCAAGGUCUAGGUACAG 3052 2256 GAACCUUU G UCCACCAU 1140 AUGGUGGAGCCGAAAGGCGAGUCAAGGUCU AAAGGUUC 3053 2346 CUUGGCGU G UGUCCCUG 1141CAGGGACA GCCGAAAGGCGAGUCAAGGUCU ACGCCAAG 3054 2348 UGGCGUGU G UCCCUGUG1142 CACAGGGA GCCGAAAGGCGAGUCAAGGUCU ACACGCCA 3055 2354 GUGUCCCU GUGGUACCC 1143 GGGUACCA GCCGAAAGGCGAGUCAAGGUCU AGGGACAC 3056 2385CCAAGCUU G UUUCCCUG 1144 CAGGGAAA GCCGAAAGGCGAGUCAAGGUCU AAGCUUGG 30572453 CAGGGACU G UAUAAACA 1145 UGUUUAUA GCCGAAAGGCGAGUCAAGGUCU AGUCCCUG3058 14 CGUCCGCA G CCCGCCCG 1146 CGGGCGGG GCCGAAAGGCGAGUCAAGGUCUUGCGGACG 3059 26 GCCCGGGA G CUGCGAGC 1147 GCUCGCAGGCCGAAAGGCGAGUCAAGGUCU UCCCGGGC 3060 33 AGCUGCGA G CCGCGAGC 1148GCUCGCGG GCCGAAAGGCGAGUCAAGGUCU UCGCAGCU 3061 40 AGCCGCGA G CUGGAUUA1149 UAAUCCAG GCCGAAAGGCGAGUCAAGGUCU UCGCGGCU 3062 51 GGAUUAUG GUGGCCUGA 1150 UCAGGCCA GCCGAAAGGCGAGUCAAGGUCU CAUAAUCC 3063 54 UUAUGGUGG CCUGAGCA 1151 UGCUCAGG GCCGAAAGGCGAGUCAAGGUCU CACCAUAA 3064 60UGGCCUGA G CAGCCAAC 1152 GUUGGCUG GCCGAAAGGCGAGUCAAGGUCU UCAGGCCA 306563 CCUGAGCA G CCAACGCA 1153 UGCGUUGG GCCGAAAGGCGAGUCAAGGUCU UGCUCAGG3066 72 CCAACGCA G CCGCAGGA 1154 UCCUGCGG GCCGAAAGGCGAGUCAAGGUCUUGCGUUGG 3067 81 CCGCAGGA G CCCGGAGC 1155 GCUCCGGGGCCGAAAGGCGAGUCAAGGUCU UCCUGCGG 3068 88 AGCCCGGA G CCCUUGCC 1156GGCAAGGG GCCGAAAGGCGAGUCAAGGUCU UCCGGGCU 3069 134 CCAGGGAA G CCGCCACC1157 GGUGGCGG GCCGAAAGGCGAGUCAAGGUCU UUCCCUGG 3070 144 CGCCACCG GCCCGCCAU 1158 AUGGCGGG GCCGAAAGGCGAGUCAAGGUCU CCGUGGCG 3071 167 CCCUCCCAG CCCCGCCG 1159 CGGCGGGG GCCGAAAGGCGAGUCAAGGUCU UGGGAGGG 3072 179CGCCGGGA G CCCGCGCC 1160 GGCGCGGG GCCGAAAGGCGAGUCAAGGUCU UCCCGGCG 3073198 CUGCCCAG G CUGGCCGC 1161 GCGGCCAG GCCGAAAGGCGAGUCAAGGUCU CUGGGCAG3074 202 CCAGGCUG G CCGCCGCC 1162 GGCGGCGG GCCGAAAGGCGAGUCAAGGUCUCAGCCUGG 3075 211 CCGCCGCC G UGCCGAUG 1163 CAUCGGCAGCCGAAAGGCGAGUCAAGGUCU GGCGGCGG 3076 222 CCGAUGUA G CGGGCUCC 1164GGAGCCCG GCCGAAAGGCGAGUCAAGGUCU UACAUCGG 3077 226 UGUAGCGG G CUCCGGAU1165 AUCCGGAG GCCGAAAGGCGAGUCAAGGUCU CCGCUACA 3078 239 GGAUCCCA GCCUCUCCC 1166 GGGAGAGG GCCGAAAGGCGAGUCAAGGUCU UGGGAUCC 3079 256 CUGCUCCCG UGCUCUGC 1167 GCAGAGCA GCCGAAAGGCGAGUCAAGGUCU GGGAGCAG 3080 290UCUCCACA G CCCGGACC 1168 GGUCCGGG GCCGAAAGGCGAGUCAAGGUCU UGUGGAGA 3081304 ACCCGGGG G CUGGCCCA 1169 UGGGCCAG GCCGAAAGGCGAGUCAAGGUCU CCCCGGGU3082 308 GGGGGCUG G CCCAGGGC 1170 GCCCUGGG GCCGAAAGGCGAGUCAAGGUCUCAGCCCCC 3083 315 GGCCCAGG G CCCUGCAG 1171 CUGCAGGGGCCGAAAGGCGAGUCAAGGUCU CCUGGGCC 3084 324 CCCUGCAG G CCCUGGCG 1172CGCCAGGG GCCGAAAGGCGAGUCAAGGUCU CUGCAGGG 3085 330 AGGCCCUG G CGUCCUGA1173 UCAGGACG GCCGAAAGGCGAGUCAAGGUCU CAGGGCCU 3086 332 GCCCUGGC GUCCUGAUG 1174 CAUCAGGA GCCGAAAGGCGAGUCAAGGUCU GCCAGGGC 3087 348 GCCCCCAAG CUCCCUCU 1175 AGAGGGAG GCCGAAAGGCGAGUCAAGGUCU UUGGGGGC 3088 365CCUGAGAA G CCACCAGC 1176 GCUGGUGG GCCGAAAGGCGAGUCAAGGUCU UUCUCAGG 3089372 AGCCACCA G CACCACCC 1177 GGGUGGUG GCCGAAAGGCGAGUCAAGGUCU UGGUGGCU3090 391 ACUUGGGG G CAGGCGCC 1178 GGCGCCUG GCCGAAAGGCGAGUCAAGGUCUCCCCAAGU 3091 395 GGGGGCAG G CGCCAGGG 1179 CCCUGGCGGCCGAAAGGCGAGUCAAGGUCU CUGCCCCC 3092 410 GGACGGAC G UGGGCCAG 1180CUGGCCCA GCCGAAAGGCGAGUCAAGGUCU GUCCGUCC 3093 414 GGACGUGG G CCAGUGCG1181 CGCACUGG GCCGAAAGGCGAGUCAAGGUCU CCACGUCC 3094 418 GUGGGCCA GUGCGAGCC 1182 GGCUCGCA GCCGAAAGGCGAGUCAAGGUCU UGGCCCAC 3095 424 CAGUGCGAG CCCAGAGG 1183 CCUCUGGG GCCGAAAGGCGAGUCAAGGUCU UCGCACUG 3096 433CCCAGAGG G CCCGAAGG 1184 CCUUCGGG GCCGAAAGGCGAGUCAAGGUCU CCUCUGGG 3097441 GCCCGAAG G CCGGGGCC 1185 GGCCCCGG GCCGAAAGGCGAGUCAAGGUCU CUUCGGGC3098 447 AGGCCGGG G CCCACCAU 1186 AUGGUGGG GCCGAAAGGCGAGUCAAGGUCUCCCGGCCU 3099 457 CCACCAUG G CCCAAGCC 1187 GGCUUGGGGCCGAAAGGCGAGUCAAGGUCU CAUGGUGG 3100 463 UGGCCCAA G CCCUGCCC 1188GGGCAGGG GCCGAAAGGCGAGUCAAGGUCU UUGGGCCA 3101 474 CUGCCCUG G CUCCUGCU1189 AGCAGGAG GCCGAAAGGCGAGUCAAGGUCU CAGGGCAG 3102 491 GUGGAUGG GCGCGGGAG 1190 CUCCCGCG GCCGAAAGGCGAGUCAAGGUCU CCAUCCAC 3103 499 GCGCGGGAG UGCUGCCU 1191 AGGCAGCA GCCGAAAGGCGAGUCAAGGUCU UCCCGCGC 3104 515UGCCCACG G CACCCAGC 1192 GCUGGGUG GCCGAAAGGCGAGUCAAGGUCU CGUGGGCA 3105522 GGCACCCA G CACGGCAU 1193 AUGCCGUG GCCGAAAGGCGAGUCAAGGUCU UGGGUGCC3106 527 CCAGCACG G CAUCCGGC 1194 GCCGGAUG GCCGAAAGGCGAGUCAAGGUCUCGUGCUGG 3107 534 GGCAUCCG G CUGCCCCU 1195 AGGGGCAGGCCGAAAGGCGAGUCAAGGUCU CGGAUGCC 3108 548 CCUGCGCA G CGGCCUGG 1196CCAGGCCG GCCGAAAGGCGAGUCAAGGUCU UGCGCAGG 3109 551 GCGCAGCG G CCUGGGGG1197 CCCCCAGG GCCGAAAGGCGAGUCAAGGUCU CGCUGCGC 3110 560 CCUGGGGG GCGCCCCCC 1198 GGGGGGCG GCCGAAAGGCGAGUCAAGGUCU CCCCCAGG 3111 573 CCCCUGGGG CUGCGGCU 1199 AGCCGCAG GCCGAAAGGCGAGUCAAGGUCU CCCAGGGG 3112 579GGGCUGCG G CUGCCCCG 1200 CGGGGCAG GCCGAAAGGCGAGUCAAGGUCU CGCAGCCC 3113603 GACGAAGA G CCCGAGGA 1201 UCCUCGGG GCCGAAAGGCGAGUCAAGGUCU UCUUCGUC3114 612 CCCGAGGA G CCCGGCCG 1202 CGGCCGGG GCCGAAAGGCGAGUCAAGGUCUUCCUCGGG 3115 617 GGAGCCCG G CCGGAGGG 1203 CCCUCCGGGCCGAAAGGCGAGUCAAGGUCU CGGGCUCC 3116 626 CCGGAGGG G CAGCUUUG 1204CAAAGCUG GCCGAAAGGCGAGUCAAGGUCU CCCUCCGG 3117 629 GAGGGGCA G CUUUGUGG1205 CCACAAAG GCCGAAAGGCGAGUCAAGGUCU UGCCCCUC 3118 643 UGGAGAUG GUGGACAAC 1206 GUUGUCCA GCCGAAAGGCGAGUCAAGGUCU CAUCUCCA 3119 659 CCUGAGGGG CAAGUCGG 1207 CCGACUUG GCCGAAAGGCGAGUCAAGGUCU CCCUCAGG 3120 663AGGGGCAA G UCGGGGCA 1208 UGCCCCGA GCCGAAAGGCGAGUCAAGGUCU UUGCCCCU 3121669 AAGUCGGG G CAGGGCUA 1209 UAGCCCUG GCCGAAAGGCGAGUCAAGGUCU CCCGACUU3122 674 GGGGCAGG G CUACUACG 1210 CGUAGUAG GCCGAAAGGCGAGUCAAGGUCUCCUGCCCC 3123 682 GCUACUAC G UGGAGAUG 1211 CAUCUCCAGCCGAAAGGCGAGUCAAGGUCU GUAGUAGC 3124 694 AGAUGACC G UGGGCAGC 1212GCUGCCCA GCCGAAAGGCGAGUCAAGGUCU GGUCAUCU 3125 698 GACCGUGG G CAGCCCCC1213 GGGGGCUG GCCGAAAGGCGAGUCAAGGUCU CCACGGUC 3126 701 CGUGGGCA GCCCCCCGC 1214 GCGGGGGG GCCGAAAGGCGAGUCAAGGUCU UGCCCACG 3127 727 ACAUCCUGG UGGAUACA 1215 UGUAUCCA GCCGAAAGGCGAGUCAAGGUCU CAGGAUGU 3128 737GGAUACAG G CAGCAGUA 1216 UACUGCUG GCCGAAAGGCGAGUCAAGGUCU CUGUAUCC 3129740 UACAGGCA G CAGUAACU 1217 AGUUACUG GCCGAAAGGCGAGUCAAGGUCU UGCCUGUA3130 743 AGGCAGCA G UAACUUUG 1218 CAAAGUUA GCCGAAAGGCGAGUCAAGGUCUUGCUGCCU 3131 754 ACUUUGCA G UGGGUGCU 1219 AGCACCCAGCCGAAAGGCGAGUCAAGGUCU UGCAAAGU 3132 758 UGCAGUGG G UGCUGCCC 1220GGGCAGCA GCCGAAAGGCGAGUCAAGGUCU CCACUGCA 3133 798 UACCAGAG G CAGCUGUC1221 GACAGCUG GCCGAAAGGCGAGUCAAGGUCU CUCUGGUA 3134 801 CAGAGGCA GCUGUCCAG 1222 CUGGACAG GCCGAAAGGCGAGUCAAGGUCU UGCCUCUG 3135 809 GCUGUCCAG CACAUACC 1223 GGUAUGUG GCCGAAAGGCGAGUCAAGGUCU UGGACAGC 3136 833CCGGAAGG G UGUGUAUG 1224 CAUACACA GCCGAAAGGCGAGUCAAGGUCU CCUUCCGG 3137857 CACCCAGG G CAAGUGGG 1225 CCCACUUG GCCGAAAGGCGAGUCAAGGUCU CCUGGGUG3138 861 CAGGGCAA G UGGGAAGG 1226 CCUUCCCA GCCGAAAGGCGAGUCAAGGUCUUUGCCCUG 3139 873 GAAGGGGA G CUGGGCAC 1227 GUGCCCAGGCCGAAAGGCGAGUCAAGGUCU UCCCCUUC 3140 878 GGAGCUGG G CACCGACC 1228GGUCGGUG GCCGAAAGGCGAGUCAAGGUCU CCAGCUCC 3141 889 CCGACCUG G UAAGCAUC1229 GAUGCUUA GCCGAAAGGCGAGUCAAGGUCU CAGGUCGG 3142 893 CCUGGUAA GCAUCCCCC 1230 GGGGGAUG GCCGAAAGGCGAGUCAAGGUCU UUACCAGG 3143 905 CCCCCAUGG CCCCAACG 1231 CGUUGGGG GCCGAAAGGCGAGUCAAGGUCU CAUGGGGG 3144 913GCCCCAAC G UCACUGUG 1232 CACAGUGA GCCGAAAGGCGAGUCAAGGUCU GUUGGGGC 3145923 CACUGUGC G UGCCAACA 1233 UGUUGGCA GCCGAAAGGCGAGUCAAGGUCU UCACAGUG3146 957 UCAGACAA G UUCUUCAU 1234 AUGAAGAA GCCGAAAGGCGAGUCAAGGUCUUUGUCUGA 3147 971 CAUCAACG G CUCCAACU 1235 AGUUGGAGGCCGAAAGGCGAGUCAAGGUCU CGUUGAUG 3148 986 CUGGGAAG G CAUCCUGG 1236CCAGGAUG GCCGAAAGGCGAGUCAAGGUCU CUUCCCAG 3149 996 AUCCUGGG G CUGGCCUA1237 UAGGCCAG GCCGAAAGGCGAGUCAAGGUCU CCCAGGAU 3150 1000 UGGGGCUG GCCUAUGCU 1238 AGCAUAGG GCCGAAAGGCGAGUCAAGGUCU CAGCCCCA 3151 1020AUUGCCAG G CCUGACGA 1239 UCGUCAGG GCCGAAAGGCGAGUCAAGGUCU CUGGCAAU 31521038 UCCCUGGA G CCUUUCUU 1240 AAGAAAGG GCCGAAAGGCGAGUCAAGGUCU UCCAGGGA3153 1057 ACUCUCUG G UAAAGCAG 1241 CUGCUUUA GCCGAAAGGCGAGUCAAGGUCUCAGAGAGU 3154 1062 CUGGUAAA G CAGACCCA 1242 UGGGUCUGGCCGAAAGGCGAGUCAAGGUCU UUUACCAG 3155 1072 AGACCCAC G UUCCCAAC 1243GUUGGGAA GCCGAAAGGCGAGUCAAGGUCU GUGGGUCU 3156 1095 UCCCUGCA G CUUUGUGG1244 CCACAAAG GCCGAAAGGCGAGUCAAGGUCU UGCAGGGA 3157 1103 GCUUUGUG GUGCUGGCU 1245 AGCCAGCA GCCGAAAGGCGAGUCAAGGUCU CACAAAGC 3158 1109UGGUGCUG G CUUCCCCC 1246 GGGGGAAG GCCGAAAGGCGAGUCAAGGUCU CAGCACCA 31591125 CUCAACCA G UCUGAAGU 1247 ACUUCAGA GCCGAAAGGCGAGUCAAGGUCU UGGUUGAG3160 1132 AGUCUGAA G UGCUGGCC 1248 GGCCAGCA GCCGAAAGGCGAGUCAAGGUCUUUCAGACU 3161 1138 AAGUGCUG G CCUCUGUC 1249 GACAGAGGGCCGAAAGGCGAGUCAAGGUCU CAGCACUU 3162 1154 CGGAGGGA G CAUGAUCA 1250UGAUCAUG GCCGAAAGGCGAGUCAAGGUCU UCCCUCCG 3163 1169 CAUUGGAG G UAUCGACC1251 GGUCGAUA GCCGAAAGGCGAGUCAAGGUCU CUCCAAUG 3164 1193 GUACACAG GCAGUCUCU 1252 AGAGACUG GCCGAAAGGCGAGUCAAGGUCU CUGUGUAC 3165 1196CACAGGCA G UCUCUGGU 1253 ACCAGAGA GCCGAAAGGCGAGUCAAGGUCU UGCCUGUG 31661203 AGUCUCUG G UAUACACC 1254 GGUGUAUA GCCGAAAGGCGAGUCAAGGUCU CAGAGACU3167 1218 CCCAUCCG G CGGGAGUG 1255 CACUCCCG GCCGAAAGGCGAGUCAAGGUCUCGGAUGGG 3168 1224 CGGCGGGA G UGGUAUUA 1256 UAAUACCAGCCGAAAGGCGAGUCAAGGUCU UCCCGCCG 3169 1227 CGGGAGUG G UAUUAUGA 1257UCAUAAUA GCCGAAAGGCGAGUCAAGGUCU CACUCCCG 3170 1237 AUUAUGAG G UGAUCAUU1258 AAUGAUCA GCCGAAAGGCGAGUCAAGGUCU CUCAUAAU 3171 1252 UUGUGCGG GUGGAGAUC 1259 GAUCUCCA GCCGAAAGGCGAGUCAAGGUCU CCGCACAA 3172 1293UGCAAGGA G UACAACUA 1260 UAGUUGUA GCCGAAAGGCGAGUCAAGGUCU UCCUUGCA 31731310 UGACAAGA G CAUUGUGG 1261 CCACAAUG GCCGAAAGGCGAGUCAAGGUCU UCUUGUCA3174 1322 UGUGGACA G UGGCACCA 1262 UGGUGCCA GCCGAAAGGCGAGUCAAGGUCUUGUCCACA 3175 1325 GGACAGUG G CACCACCA 1263 UGGUGGUGGCCGAAAGGCGAGUCAAGGUCU CACUGUCC 3176 1340 CAACCUUC G UUUGCCCA 1264UGGGCAAA GCCGAAAGGCGAGUCAAGGUCU GAAGGUUG 3177 1354 CCAAGAAA G UGUUUGAA1265 UUCAAACA GCCGAAAGGCGAGUCAAGGUCU UUUCUUGG 3178 1363 UGUUUGAA GCUGCAGUC 1266 GACUGCAG GCCGAAAGGCGAGUCAAGGUCU UUCAAACA 3179 1369AAGCUGCA G UCAAAUCC 1267 GGAUUUGA GCCGAAAGGCGAGUCAAGGUCU UGCAGCUU 31801384 CCAUCAAG G CAGCCUCC 1268 GGAGGCUG GCCGAAAGGCGAGUCAAGGUCU CUUGAUGG3181 1387 UCAAGGCA G CCUCCUCC 1269 GGAGGAGG GCCGAAAGGCGAGUCAAGGUCUUGCCUUGA 3182 1404 ACGGAGAA G UUCCCUGA 1270 UCAGGGAAGCCGAAAGGCGAGUCAAGGUCU UUCUCCGU 3183 1415 CCCUGAUG G UUUCUGGC 1271GCCAGAAA GCCGAAAGGCGAGUCAAGGUCU CAUCAGGG 3184 1422 GGUUUCUG G CUAGGAGA1272 UCUCCUAG GCCGAAAGGCGAGUCAAGGUCU CAGAAACC 3185 1431 CUAGGAGA GCAGCUGGU 1273 ACCAGCUG GCCGAAAGGCGAGUCAAGGUCU UCUCCUAG 3186 1434GGAGAGCA G CUGGUGUG 1274 CACACCAG GCCGAAAGGCGAGUCAAGGUCU UGCUCUCC 31871438 AGCAGCUG G UGUGCUGG 1275 CCAGCACA GCCGAAAGGCGAGUCAAGGUCU CAGCUGCU3188 1446 GUGUGCUG G CAAGCAGG 1276 CCUGCUUG GCCGAAAGGCGAGUCAAGGUCUCAGCACAC 3189 1450 GCUGGCAA G CAGGCACC 1277 GGUGCCUGGCCGAAAGGCGAGUCAAGGUCU UUGCCAGC 3190 1454 GCAAGCAG G CACCACCC 1278GGGUGGUG GCCGAAAGGCGAGUCAAGGUCU CUGCUUGC 3191 1480 UUUUCCCA G UCAUCUCA1279 UGAGAUGA GCCGAAAGGCGAGUCAAGGUCU UGGGAAAA 3192 1502 CCUAAUGG GUGAGGUUA 1280 UAACCUCA GCCGAAAGGCGAGUCAAGGUCU CCAUUAGG 3193 1507UGGGUGAG G UUACCAAC 1281 GUUGGUAA GCCGAAAGGCGAGUCAAGGUCU CUCACCCA 31941518 ACCAACCA G UCCUUCCG 1282 CGGAAGGA GCCGAAAGGCGAGUCAAGGUCU UGGUUGGU3195 1545 CUUCCGCA G CAAUACCU 1283 AGGUAUUG GCCGAAAGGCGAGUCAAGGUCUUGCGGAAG 3196 1557 UACCUGCG G CCAGUGGA 1284 UCCACUGGGCCGAAAGGCGAGUCAAGGUCU CGCAGGUA 3197 1561 UGCGGCCA G UGGAAGAU 1285AUCUUCCA GCCGAAAGGCGAGUCAAGGUCU UGGCCGCA 3198 1573 AAGAUGUG G CCACGUCC1286 GGACGUGG GCCGAAAGGCGAGUCAAGGUCU CACAUCUU 3199 1578 GUGGCCAC GUCCCAAGA 1287 UCUUGGGA GCCGAAAGGCGAGUCAAGGUCU GUGGCCAC 3200 1599UGUUACAA G UUUGCCAU 1288 AUGGCAAA GCCGAAAGGCGAGUCAAGGUCU UUGUAACA 32011614 AUCUCACA G UCAUCCAC 1289 GUGGAUGA GCCGAAAGGCGAGUCAAGGUCU UGUGAGAU3202 1625 AUCCACGG G CACUGUUA 1290 UAACAGUG GCCGAAAGGCGAGUCAAGGUCUCCGUGGAU 3203 1639 UUAUGGGA G CUGUUAUC 1291 GAUAACAGGCCGAAAGGCGAGUCAAGGUCU UCCCAUAA 3204 1655 CAUGGAGG G CUUCUACG 1292CGUAGAAG GCCGAAAGGCGAGUCAAGGUCU CCUCCAUG 3205 1663 GCUUCUAC G UUGUCUUU1293 AAAGACAA GCCGAAAGGCGAGUCAAGGUCU GUAGAAGC 3206 1678 UUGAUCGG GCCCGAAAA 1294 UUUUCGGG GCCGAAAGGCGAGUCAAGGUCU CCGAUCAA 3207 1694ACGAAUUG G CUUUGCUG 1295 CAGCAAAG GCCGAAAGGCGAGUCAAGGUCU CAAUUCGU 32081706 UGCUGUCA G CGCUUGCC 1296 GGCAAGCG GCCGAAAGGCGAGUCAAGGUCU UGACAGCA3209 1728 CACGAUGA G UCCAGGAC 1297 GUCCUGAA GCCGAAAGGCGAGUCAAGGUCUUCAUCGUG 3210 1738 UCAGGACG G CAGCGGUG 1298 CACCGCUGGCCGAAAGGCGAGUCAAGGUCU CGUCCUGA 3211 1741 GGACGGCA G CGGUGGAA 1299UUCCACCG GCCGAAAGGCGAGUCAAGGUCU UGCCGUCC 3212 1744 CGGCAGCG G UGGAAGGC1300 GCCUUCCA GCCGAAAGGCGAGUCAAGGUCU CGCUGCCG 3213 1751 GGUGGAAG GCCCUUUUG 1301 CAAAAGGG GCCGAAAGGCGAGUCAAGGUCU CUUCCACC 3214 1784AGACUGUG G CUACAACA 1302 UGUUGUAG GCCGAAAGGCGAGUCAAGGUCU CACAGUCU 32151809 ACAGAUGA G UCAACCCU 1303 AGGGUUGA GCCGAAAGGCGAGUCAAGGUCU UCAUCUGU3216 1828 UGACCAUA G CCUAUGUC 1304 GACAUAGG GCCGAAAGGCGAGUCAAGGUCUUAUGGUCA 3217 1840 AUGUCAUG G CUGCCAUC 1305 GAUGGCAGGCCGAAAGGCGAGUCAAGGUCU CAUGACAU 3218 1882 GCCUCAUG G UGUGUCAG 1306CUGACACA GCCGAAAGGCGAGUCAAGGUCU CAUGAGGC 3219 1890 GUGUGUCA G UGGCGCUG1307 CAGCGCCA GCCGAAAGGCGAGUCAAGGUCU UGACACAC 3220 1893 UGUCAGUG GCGCUGCCU 1308 AGGCAGCG GCCGAAAGGCGAGUCAAGGUCU CACUGACA 3221 1917CUGCGCCA G CAGCAUGA 1309 UCAUGCUG GCCGAAAGGCGAGUCAAGGUCU UGGCGCAG 32221920 CGCCAGCA G CAUGAUGA 1310 UCAUCAUG GCCGAAAGGCGAGUCAAGGUCU UGCUGGCG3223 1956 CUGCUGAA G UGAGGAGG 1311 CCUCCUCA GCCGAAAGGCGAGUCAAGGUCUUUCAGCAG 3224 1964 GUGAGGAG G CCCAUGGG 1312 CCCAUGGGGCCGAAAGGCGAGUCAAGGUCU CUCCUCAC 3225 1972 GCCCAUGG G CAGAAGAU 1313AUCUUCUG GCCGAAAGGCGAGUCAAGGUCU CCAUGGGC 3226 2006 ACACCUCC G UGGUUCAC1314 GUGAACCA GCCGAAAGGCGAGUCAAGGUCU GGAGGUGU 3227 2009 CCUCCGUG GUUCACUUU 1315 AAAGUGAA GCCGAAAGGCGAGUCAAGGUCU CACGGAGG 3228 2019UCACUUUG G UCACAAGU 1316 ACUUGUGA GCCGAAAGGCGAGUCAAGGUCU CAAAGUGA 32292026 GGUCACAA G UAGGAGAC 1317 GUCUCCUA GCCGAAAGGCGAGUCAAGGUCU UUGUGACC3230 2042 CACAGAUG G CACCUGUG 1318 CACAGGUG GCCGAAAGGCGAGUCAAGGUCUCAUCUGUG 3231 2051 CACCUGUG G CCAGAGCA 1319 UGCUCUGGGCCGAAAGGCGAGUCAAGGUCU CACAGGUG 3232 2057 UGGCCAGA G CACCUCAG 1320CUGAGGUG GCCGAAAGGCGAGUCAAGGUCU UCUGGCCA 3233 2114 AGGAAAAG G CUGGCAAG1321 CUUGCCAG GCCGAAAGGCGAGUCAAGGUCU CUUUUCCU 3234 2118 AAAGGCUG GCAAGGUGG 1322 CCACCUUG GCCGAAAGGCGAGUCAAGGUCU CAGCCUUU 3235 2123CUGGCAAG G UGGGUUCC 1323 GGAACCCA GCCGAAAGGCGAGUCAAGGUCU CUUGCCAG 32362127 CAAGGUGG G UUCCAGGG 1324 CCCUGGAA GCCGAAAGGCGAGUCAAGGUCU CCACCUUG3237 2172 AGAAAGAA G CACUCUGC 1325 GCAGAGUG GCCGAAAGGCGAGUCAAGGUCUUUCUUUCU 3238 2183 CUCUGCUG G CGGGAAUA 1326 UAUUCCCGGCCGAAAGGCGAGUCAAGGUCU CAGCAGAG 3239 2198 UACUCUUG G UCACCUCA 1327UGAGGUGA GCCGAAAGGCGAGUCAAGGUCU CAAGAGUA 3240 2214 AAAUUUAA G UCGGGAAA1328 UUUCCCGA GCCGAAAGGCGAGUCAAGGUCU UUAAAUUU 3241 2243 AAACUUCA GCCCUGAAC 1329 GUUCAGGG GCCGAAAGGCGAGUCAAGGUCU UGAAGUUU 3242 2288AACCCAAA G UAUUCUUC 1330 GAAGAAUA GCCGAAAGGCGAGUCAAGGUCU UUUGGGUU 32432305 UUUUCUUA G UUUCAGAA 1331 UUCUGAAA GCCGAAAGGCGAGUCAAGGUCU UAAGAAAA3244 2314 UUUCAGAA G UACUGGCA 1332 UGCCAGUA GCCGAAAGGCGAGUCAAGGUCUUUCUGAAA 3245 2320 AAGUACUG G CAUCACAC 1333 GUGUGAUGGCCGAAAGGCGAGUCAAGGUCU CAGUACUU 3246 2333 ACACGCAG G UUACCUUG 1334CAAGGUAA GCCGAAAGGCGAGUCAAGGUCU CUGCGUGU 3247 2342 UUACCUUG G CGUGUGUC1335 GACACACG GCCGAAAGGCGAGUCAAGGUCU CAAGGUAA 3248 2344 ACCUUGGC GUGUGUCCC 1336 GGGACACA GCCGAAAGGCGAGUCAAGGUCU GCCAAGGU 3249 2357UCCCUGUG G UACCCUGG 1337 CCAGGGUA GCCGAAAGGCGAGUCAAGGUCU CACAGGGA 32502365 GUACCCUG G CAGAGAAG 1338 CUUCUCUG GCCGAAAGGCGAGUCAAGGUCU CAGGGUAC3251 2381 GAGACCAA G CUUGUUUC 1339 GAAACAAG GCCGAAAGGCGAGUCAAGGUCUUUGGUCUC 3252 2397 CCCUGCUG G CCAAAGUC 1340 GACUUUGGGCCGAAAGGCGAGUCAAGGUCU CAGCAGGG 3253 2403 UGGCCAAA G UCAGUAGG 1341CCUACUGA GCCGAAAGGCGAGUCAAGGUCU UUUGGCCA 3254 2407 CAAAGUCA G UAGGAGAG1342 CUCUCCUA GCCGAAAGGCGAGUCAAGGUCU UGACUUUG 3255 2424 GAUGCACA GUUUGCUAU 1343 AUAGCAAA GCCGAAAGGCGAGUCAAGGUCU UGUGCAUC 3256 2463AUAAACAA G CCUAACAU 1344 AUGUUAGG GCCGAAAGGCGAGUCAAGGUCU UUGUUUAU 32572474 UAACAUUG G UGCAAAGA 1345 UCUUUGCA GCCGAAAGGCGAGUCAAGGUCU CAAUGUUA3258

[0308] TABLE VII Human BACE DNAzyme and Target Sequence Pos SubstrateSeq ID DNAzyme Seq ID 48 GCUGGAUU A UGGUGGCC 3 GGCCACCA GGCTAGCTACAACGAAATCCAGC 3259 677 GCAGGGCU A CUACGUGG 27 CCACGTAG GGCTAGCTACAACGAAGCCCTGC 3260 680 GGGCUACU A CGUGGAGA 28 TCTCCACG GGCTAGCTACAACGAAGTAGCCC 3261 733 UGGUGGAU A CAGGCAGC 31 GCTGCCTG GGCTAGCTACAACGAATCCACCA 3262 788 GCAUCGCU A CUACCAGA 38 TCTGGTAG GGCTAGCTACAACGAAGCGATGC 3263 791 UCGCUACU A CCAGAGGC 39 GCCTCTGG GGCTAGCTACAACGAAGTAGCGA 3264 815 CAGCACAU A CCGGGACC 41 GGTCCCGG GGCTAGCTACAACGAATGTGCTG 3265 839 GGGUGUGU A UGUGCCCU 43 AGGGCACA GGCTAGCTACAACGAACACACCC 3266 848 UGUGCCCU A CACCCAGG 44 CCTGGGTG GGCTAGCTACAACGAAGGGCACA 3267 1004 GCUGGCCU A UGCUGAGA 58 TCTCAGCA GGCTAGCTACAACGAAGGCCAGC 3268 1171 UUGGAGGU A UCGACCAC 85 GTGGTCGA GGCTAGCTACAACGAACCTCCAA 3269 1187 CUCGCUGU A CACAGGCA 88 TGCCTGTG GGCTAGCTACAACGAACAGCGAG 3270 1205 UCUCUGGU A UACACCCA 91 TGGGTGTA GGCTAGCTACAACGAACCAGAGA 3271 1207 UCUGGUAU A CACCCAUC 92 GATGGGTG GGCTAGCTACAACGAATACCAGA 3272 1229 GGAGUGGU A UUAUGAGG 94 CCTCATAA GGCTAGCTACAACGAACCACTCC 3273 1232 GUGGUAUU A UGAGGUGA 96 TCACCTCA GGCTAGCTACAACGAAATACCAC 3274 1295 CAAGGAGU A CAACUAUG 101 CATAGTTG GGCTAGCTACAACGAACTCCTTG 3275 1301 GUACAACU A UGACAAGA 102 TCTTGTCA GGCTAGCTACAACGAAGTTGTAC 3276 1493 CUCACUCU A CCUAAUGG 130 CCATTAGG GGCTAGCTACAACGAAGAGTGAG 3277 1510 GUGAGGUU A CCAACCAG 133 CTGGTTGG GGCTAGCTACAACGAAACCTCAC 3278 1550 GCAGCAAU A CCUGCGGC 141 GCCGCAGG GGCTAGCTACAACGAATTGCTGC 3279 1595 CGACUGUU A CAAGUUUG 144 CAAACTTG GGCTAGCTACAACGAAACAGTCG 3280 1633 GCACUGUU A UGGGAGCU 152 AGCTCCCA GGCTAGCTACAACGAAACAGTGC 3281 1645 GAGCUGUU A UCAUGGAG 154 CTCCATGA GGCTAGCTACAACGAAACAGCTC 3282 1661 GGGCUUCU A CGUUGUCU 158 AGACAACG GGCTAGCTACAACGAAGAAGCCC 3283 1787 CUGUGGCU A CAACAUUC 176 GAATGTTG GGCTAGCTACAACGAAGCCACAG 3284 1832 CAUAGCCU A UGUCAUGG 182 CCATGACA GGCTAGCTACAACGAAGGCTATG 3285 2141 GGGACUGU A CCUGUAGG 212 CCTACAGG GGCTAGCTACAACGAACAGTCCC 3286 2191 GCGGGAAU A CUCUUGGU 215 ACCAAGAG GGCTAGCTACAACGAATTCCCGC 3287 2290 CCCAAAGU A UUCUUCUU 240 AAGAAGAA GGCTAGCTACAACGAACTTTGGG 3288 2316 UCAGAAGU A CUGGCAUC 254 GATGCCAG GGCTAGCTACAACGAACTTCTGA 3289 2336 CGCAGGUU A CCUUGGCG 257 CGCCAAGG GGCTAGCTACAACGAAACCTGCG 3290 2359 CCUGUGGU A CCCUGGCA 260 TGCCAGGG GGCTAGCTACAACGAACCACAGG 3291 2431 AGUUUGCU A UUUGCUUU 269 AAAGCAAA GGCTAGCTACAACGAAGCAAACT 3292 2455 GGGACUGU A UAAACAAG 275 CTTGTTTA GGCTAGCTACAACGAACAGTCCC 3293 140 AAGCCGCC A CCGGCCCG 322 CGGGCCGG GGCTAGCTACAACGAGGCGGCTT 3294 151 GGCCCGCC A UGCCCGCC 327 GGCGGGCA GGCTAGCTACAACGAGGCGGGCC 3295 287 CGCUCUCC A CAGCCCGG 380 CCGGGCTG GGCTAGCTACAACGAGGAGAGCG 3296 368 GAGAAGCC A CCAGCACC 412 GGTGCTGG GGCTAGCTACAACGAGGCTTCTC 3297 374 CCACCAGC A CCACCCAG 415 CTGGGTGG GGCTAGCTACAACGAGCTGGTGG 3298 377 CCAGCACC A CCCAGACU 417 AGTCTGGG GGCTAGCTACAACGAGGTGCTGG 3299 451 CGGGGCCC A CCAUGGCC 435 GGCCATGG GGCTAGCTACAACGAGGGCCCCG 3300 454 GGCCCACC A UGGCCCAA 437 TTGGGCCA GGCTAGCTACAACGAGGTGGGCC 3301 512 GCCUGCCC A CGGCACCC 456 GGGTGCCG GGCTAGCTACAACGAGGGCAGGC 3302 517 CCCACGGC A CCCAGCAC 457 GTGCTGGG GGCTAGCTACAACGAGCCGTGGG 3303 524 CACCCAGC A CGGCAUCC 461 GGATGCCG GGCTAGCTACAACGAGCTGGGTG 3304 529 AGCACGGC A UCCGGCUG 462 CAGCCGGA GGCTAGCTACAACGAGCCGTGCT 3305 721 CGCUCAAC A UCCUGGUG 508 CACCAGGA GGCTAGCTACAACGAGTTGAGCG 3306 770 UGCCCCCC A CCCCUUCC 522 GGAAGGGG GGCTAGCTACAACGAGGGGGGCA 3307 782 CUUCCUGC A UCGCUACU 529 AGTAGCGA GGCTAGCTACAACGAGCAGGAAG 3308 811 UGUCCAGC A CAUACCGG 538 CCGGTATG GGCTAGCTACAACGAGCTGGACA 3309 813 UCCAGCAC A UACCGGGA 539 TCCCGGTA GGCTAGCTACAACGAGTGCTGGA 3310 850 UGCCCUAC A CCCAGGGC 547 GCCCTGGG GGCTAGCTACAACGAGTAGGGCA 3311 880 AGCUGGGC A CCGACCUG 553 CAGGTCGG GGCTAGCTACAACGAGCCCAGCT 3312 895 UGGUAAGC A UCCCCCAU 557 ATGGGGGA GGCTAGCTACAACGAGCTTACCA 3313 902 CAUCCCCC A UGGCCCCA 562 TGGGGCCA GGCTAGCTACAACGAGGGGGATG 3314 916 CCAACGUC A CUGUGCGU 567 ACGCACAG GGCTAGCTACAACGAGACGTTGG 3315 931 GUGCCAAC A UUGCUGCC 571 GGCAGCAA GGCTAGCTACAACGAGTTGGCAC 3316 940 UUGCUGCC A UCACUGAA 574 TTCAGTGA GGCTAGCTACAACGAGGCAGCAA 3317 943 CUGCCAUC A CUGAAUCA 575 TGATTCAG GGCTAGCTACAACGAGATGGCAG 3318 964 AGUUCUUC A UCAACGGC 580 GCCGTTGA GGCTAGCTACAACGAGAAGAACT 3319 988 GGGAAGGC A UCCUGGGG 586 CCCCAGGA GGCTAGCTACAACGAGCCTTCCC 3320 1070 GCAGACCC A CGUUCCCA 610 TGGGAACG GGCTAGCTACAACGAGGGTCTGC 3321 1156 GAGGGAGC A UGAUCAUU 638 AATGATCA GGCTAGCTACAACGAGCTCCCTC 3322 1162 GCAUGAUC A UUGGAGGU 639 ACCTCCAA GGCTAGCTACAACGAGATCATGC 3323 1178 UAUCGACC A CUCGCUGU 641 ACAGCGAG GGCTAGCTACAACGAGGTCGATA 3324 1189 CGCUGUAC A CAGGCAGU 644 ACTGCCTG GGCTAGCTACAACGAGTACAGCG 3325 1209 UGGUAUAC A CCCAUCCG 649 CGGATGGG GGCTAGCTACAACGAGTATACCA 3326 1213 AUACACCC A UCCGGCGG 652 CCGCCGGA GGCTAGCTACAACGAGGGTGTAT 3327 1243 AGGUGAUC A UUGUGCGG 654 CCGCACAA GGCTAGCTACAACGAGATCACCT 3328 1312 ACAAGAGC A UUGUGGAC 663 GTCCACAA GGCTAGCTACAACGAGCTCTTGT 3329 1327 ACAGUGGC A CCACCAAC 665 GTTGGTGG GGCTAGCTACAACGAGCCACTGT 3330 1330 GUGGCACC A CCAACCUU 667 AAGGTTGG GGCTAGCTACAACGAGGTGCCAC 3331 1378 UCAAAUCC A UCAAGGCA 679 TGCCTTGA GGCTAGCTACAACGAGGATTTGA 3332 1396 CCUCCUCC A CGGAGAAG 687 CTTCTCCG GGCTAGCTACAACGAGGAGGAGG 3333 1456 AAGCAGGC A CCACCCCU 698 AGGGGTGG GGCTAGCTACAACGAGCCTGCTT 3334 1459 CAGGCACC A CCCCUUGG 700 CCAAGGGG GGCTAGCTACAACGAGGTGCCTG 3335 1471 CUUGGAAC A UUUUCCCA 705 TGGGAAAA GGCTAGCTACAACGAGTTCCAAG 3336 1483 UCCCAGUC A UCUCACUC 709 GAGTGAGA GGCTAGCTACAACGAGACTGGGA 3337 1488 GUCAUCUC A CUCUACCU 711 AGGTAGAG GGCTAGCTACAACGAGAGATGAC 3338 1528 CCUUCCGC A UCACCAUC 723 GATGGTGA GGCTAGCTACAACGAGCGGAAGG 3339 1531 UCCGCAUC A CCAUCCUU 724 AAGGATGG GGCTAGCTACAACGAGATGCGGA 3340 1534 GCAUCACC A UCCUUCCG 726 CGGAAGGA GGCTAGCTACAACGAGGTGATGC 3341 1576 AUGUGGCC A CGUCCCAA 737 TTGGGACG GGCTAGCTACAACGAGGCCACAT 3342 1606 AGUUUGCC A UCUCACAG 744 CTGTGAGA GGCTAGCTACAACGAGGCAAACT 3343 1611 GCCAUCUC A CAGUCAUC 746 GATGACTG GGCTAGCTACAACGAGAGATGGC 3344 1617 UCACAGUC A UCCACGGG 748 CCCGTGGA GGCTAGCTACAACGAGACTGTGA 3345 1621 AGUCAUCC A CGGGCACU 750 AGTGCCCG GGCTAGCTACAACGAGGATGACT 3346 1627 CCACGGGC A CUGUUAUG 751 CATAACAG GGCTAGCTACAACGAGCCCGTGG 3347 1648 CUGUUAUC A UGGAGGGC 754 GCCCTCCA GGCTAGCTACAACGAGATAACAG 3348 1715 CGCUUGCC A UGUGCACG 765 CGTGCACA GGCTAGCTACAACGAGGCAAGCG 3349 1721 CCAUGUGC A CGAUGAGU 766 ACTCATCG GGCTAGCTACAACGAGCACATGG 3350 1762 CUUUUGUC A CCUUGGAC 772 GTCCAAGG GGCTAGCTACAACGAGACAAAAG 3351 1771 CCUUGGAC A UGGAAGAC 775 GTCTTCCA GGCTAGCTACAACGAGTCCAAGG 3352 1792 GCUACAAC A UUCCACAG 779 CTGTGGAA GGCTAGCTACAACGAGTTGTAGC 3353 1797 AACAUUCC A CAGACAGA 781 TCTGTCTG GGCTAGCTACAACGAGGAATGTT 3354 1819 CAACCCUC A UGACCAUA 788 TATGGTCA GGCTAGCTACAACGAGAGGGTTG 3355 1825 UCAUGACC A UAGCCUAU 790 ATAGGCTA GGCTAGCTACAACGAGGTCATGA 3356 1837 CCUAUGUC A UGGCUGCC 793 GGCAGCCA GGCTAGCTACAACGAGACATAGG 3357 1846 UGGCUGCC A UCUGCGCC 796 GGCGCAGA GGCTAGCTACAACGAGGCAGCCA 3358 1861 CCCUCUUC A UGCUGCCA 802 TGGCAGCA GGCTAGCTACAACGAGAAGAGGG 3359 1869 AUGCUGCC A CUCUGCCU 805 AGGCAGAG GGCTAGCTACAACGAGGCAGCAT 3360 1879 UCUGCCUC A UGGUGUGU 810 ACACACCA GGCTAGCTACAACGAGAGGCAGA 3361 1922 CCAGCAGC A UGAUGACU 822 AGTCATCA GGCTAGCTACAACGAGCTGCTGG 3362 1942 CUGAUGAC A UCUCCCUG 825 CAGGGAGA GGCTAGCTACAACGAGTCATCAG 3363 1968 GGAGGCCC A UGGGCAGA 833 TCTGCCCA GGCTAGCTACAACGAGGGCCTCC 3364 1998 CCUGGACC A CACCUCCG 840 CGGAGGTG GGCTAGCTACAACGAGGTCCAGG 3365 2000 UGGACCAC A CCUCCGUG 841 CACGGAGG GGCTAGCTACAACGAGTGGTCCA 3366 2013 CGUGGUUC A CUUUGGUC 845 GACCAAAG GGCTAGCTACAACGAGAACCACG 3367 2022 CUUUGGUC A CAAGUAGG 847 CCTACTTG GGCTAGCTACAACGAGACCAAAG 3368 2035 UAGGAGAC A CAGAUGGC 849 GCCATCTG GGCTAGCTACAACGAGTCTCCTA 3369 2044 CAGAUGGC A CCUGUGGC 851 GCCACAGG GGCTAGCTACAACGAGCCATCTG 3370 2059 GCCACAGC A CCUCAGGA 856 TCCTGAGG GGCTAGCTACAACGAGCTCTGGC 3371 2076 CCCUCCCC A CCCACCAA 866 TTGGTGGG GGCTAGCTACAACGAGGGGAGGG 3372 2080 CCCCACCC A CCAAAUGC 869 GCATTTGG GGCTAGCTACAACGAGGGTGGGG 3373 2174 AAAGAAGC A CUCUGCUG 885 CACCAGAG GGCTAGCTACAACGAGCTTCTTT 3374 2201 UCUUGGUC A CCUCAAAU 891 ATTTGAGG GGCTAGCTACAACGAGACCAAGA 3375 2260 CUUUGUCC A CCAUUCCU 906 AGGAATGG GGCTAGCTACAACGAGGACAAAG 3376 2263 UGUCCACC A UUCCUUUA 908 TAAAGGAA GGCTAGCTACAACGAGGTGGACA 3377 2322 GUACUGGC A UCACACGC 922 GCGTGTGA GGCTAGCTACAACGAGCCAGTAC 3378 2325 CUGGCAUC A CACGCAGG 923 CCTGCGTG GGCTAGCTACAACGAGATGCCAG 3379 2327 GGCAUCAC A CGCAGGUU 924 AACCTGCG GGCTAGCTACAACGAGTGATGCC 3380 2421 GAGGAUGC A CAGUUUGC 945 GCAAACTG GGCTAGCTACAACGAGCATCCTC 3381 2470 AGCCUAAC A UUGGUGCA 954 TGCACCAA GGCTAGCTACAACGAGTTAGGCT 3382 11 ACGCGUCC G CAGCCCGC 960 GCGGGCTG GGCTAGCTACAACGAGGACGCGT 3383 18 CGCAGCCC G CCCGGGAG 961 CTCCCGGG GGCTAGCTACAACGAGGGCTGCG 3384 29 CGGGAGCU G CGAGCCGC 962 GCGGCTCG GGCTAGCTACAACGAAGCTCCCG 3385 36 UGCGAGCC G CGAGCUGG 964 CCAGCTCG GGCTAGCTACAACGAGGCTCGCA 3386 69 CAGCCAAC G CAGCCGCA 967 TGCGGCTG GGCTAGCTACAACGAGTTGGCTG 3387 75 ACGCAGCC G CAGGAGCC 968 GGCTCCTG GGCTAGCTACAACGAGGCTGCGT 3388 94 GAGCCCUU G CCCCUGCC 969 GGCAGGGG GGCTAGCTACAACGAAAGGGCTC 3389 100 UUGCCCCU G CCCGCGCC 970 GGCGCGGG GGCTAGCTACAACGAAGGGGCAA 3390 104 CCCUGCCC G CGCCGCCG 971 CGGCGGCG GGCTAGCTACAACGAGGGCAGGG 3391 106 CUGCCCGC G CCGCCGCC 972 GGCGGCGG GGCTAGCTACAACGAGCGGGCAG 3392 109 CCCGCGCC G CCGCCCGC 973 GCGGGCGG GGCTAGCTACAACGAGGCGCGGG 3393 112 GCGCCGCC G CCCGCCGG 974 CCGGCGGG GGCTAGCTACAACGAGGCGGCGC 3394 116 CGCCGCCC G CCGGGGGG 975 CCCCCCGG GGCTAGCTACAACGAGGGCGGCG 3395 137 GGGAAGCC G CCACCGGC 976 GCCGGTGG GGCTAGCTACAACGAGGCTTCCC 3396 148 ACCGGCCC G CCAUGCCC 977 GGGCATGG GGCTAGCTACAACGAGGGCCGGT 3397 153 CCCGCCAU G CCCGCCCC 978 GGGGCGGG GGCTAGCTACAACGAATGGCGGG 3398 157 CCAUGCCC G CCCCUCCC 979 GGGAGGGG GGCTAGCTACAACGAGGGCATGG 3399 172 CCAGCCCC G CCGGGAGC 980 GCTCCCGG GGCTAGCTACAACGAGGGGCTGG 3400 183 GGGAGCCC G CGCCCGCU 981 AGCGGGCG GGCTAGCTACAACGAGGGCTCCC 3401 185 GAGCCCGC G CCCGCUGC 982 GCAGCGGG GGCTAGCTACAACGAGCGGGCTC 3402 189 CCGCGCCC G CUGCCCAG 983 CTGGGCAG GGCTAGCTACAACGAGGGCGCGG 3403 192 CGCCCGCU G CCCAGGCU 984 AGCCTGGG GGCTAGCTACAACGAAGCGGGCG 3404 205 GGCUGGCC G CCGCCGUG 985 CACGGCGG GGCTAGCTACAACGAGGCCAGCC 3405 208 UGGCCGCC G CCGUGCCG 986 CGGCACGG GGCTAGCTACAACGAGGCGGCCA 3406 213 GCCGCCGU G CCGAUGUA 987 TACATCGG GGCTAGCTACAACGAACGGCGGC 3407 250 UCUCCCCU G CUCCCGUG 989 CACGGGAG GGCTAGCTACAACGAAGGGGAGA 3408 258 GCUCCCGU G CUCUGCGG 990 CCGCAGAG GGCTAGCTACAACGAACGGGAGC 3409 263 CGUGCUCU G CGGAUCUC 991 GAGATCCG GGCTAGCTACAACGAAGAGCACG 3410 280 CCCUGACC G CUCUCCAC 993 GTGGAGAG GGCTAGCTACAACGAGGTCAGGG 3411 320 AGGGCCCU G CAGGCCCU 994 AGGGCCTG GGCTAGCTACAACGAAGGGCCCT 3412 340 GUCCUGAU G CCCCCAAG 996 CTTGGGGG GGCTAGCTACAACGAATCAGGAC 3413 397 GGGCAGGC G CCAGGGAC 998 GTCCCTGG GGCTAGCTACAACGAGCCTGCCC 3414 420 GGGCCAGU G CGAGCCCA 999 TGGGCTCG GGCTAGCTACAACGAACTGGCCC 3415 468 CAAGCCCU G CCCUGGCU 1002 AGCCAGGG GGCTAGCTACAACGAAGGGCTTG 3416 480 UGGCUCCU G CUGUGGAU 1003 ATCCACAG GGCTAGCTACAACGAAGGAGCCA 3417 493 GGAUGGGC G CGGGAGUG 1004 CACTCCCG GGCTAGCTACAACGAGCCCATCC 3418 501 GCGGGAGU G CUGCCUGC 1005 GCAGGCAG GGCTAGCTACAACGAACTCCCGC 3419 504 GGAGUGCU G CCUGCCCA 1006 TGGGCAGG GGCTAGCTACAACGAAGCACTCC 3420 508 UGCUGCCU G CCCACGGC 1007 GCCGTGGG GGCTAGCTACAACGAAGGCAGCA 3421 537 AUCCGGCU G CCCCUGCG 1008 CGCAGGGG GGCTAGCTACAACGAAGCCGGAT 3422 543 CUGCCCCU G CGCAGCGG 1009 CCGCTGCG GGCTAGCTACAACGAAGGGGCAG 3423 545 GCCCCUGC G CAGCGGCC 1010 GGCCGCTG GGCTAGCTACAACGAGCAGGGGC 3424 562 UGGGGGGC G CCCCCCUG 1011 CAGGGGGG GGCTAGCTACAACGAGCCCCCCA 3425 576 CUGGGGCU G CGGCUGCC 1012 GGCAGCCG GGCTAGCTACAACGAAGCCCCAG 3426 582 CUGCGGCU G CCCCGGGA 1013 TCCCGGGG GGCTAGCTACAACGAAGCCGCAG 3427 708 AGCCCCCC G CAGACGCU 1019 AGCGTCTG GGCTAGCTACAACGAGGGGGGCT 3428 714 CCGCAGAC G CUCAACAU 1020 ATGTTGAG GGCTAGCTACAACGAGTCTGCGG 3429 751 GUAACUUU G CAGUGGGU 1021 ACCCACTG GGCTAGCTACAACGAAAAGTTAC 3430 760 CAGUGGGU G CUGCCCCC 1022 GGGGGCAG GGCTAGCTACAACGAACCCACTG 3431 763 UGGGUGCU G CCCCCCAC 1023 GTGGGGGG GGCTAGCTACAACGAAGCACCCA 3432 780 CCCUUCCU G CAUCGCUA 1024 TAGCGATG GGCTAGCTACAACGAAGGAAGGG 3433 785 CCUGCAUC G CUACUACC 1025 GGTAGTAG GGCTAGCTACAACGAGATGCAGG 3434 843 GUGUAUGU G CCCUACAC 1026 GTGTAGGG GGCTAGCTACAACGAACATACAC 3435 921 GUCACUGU G CGUGCCAA 1028 TTGGCACG GGCTAGCTACAACGAACAGTGAC 3436 925 CUGUGCGU G CCAACAUU 1029 AATGTTGG GGCTAGCTACAACGAACGCACAG 3437 934 CCAACAUU G CUGCCAUC 1030 GATGGCAG GGCTAGCTACAACGAAATGTTGG 3438 937 ACAUUGCU G CCAUCACU 1031 AGTGATGG GGCTAGCTACAACGAAGCAATGT 3439 1006 UGGCCUAU G CUGAGAUU 1033 AATCTCAG GGCTAGCTACAACGAATAGGCCA 3440 1015 CUGAGAUU G CCAGGCCU 1035 AGGCCTGG GGCTAGCTACAACGAAATCTCAG 3441 1092 UUCUCCCU G CAGCUUUG 1039 CAAAGCTG GGCTAGCTACAACGAAGGCAGAA 3442 1105 UUUGUGGU G CUGGCUUC 1040 GAAGCCAG GGCTAGCTACAACGAACCACAAA 3443 1134 UCUGAAGU G CUGGCCUC 1042 GAGGCCAG GGCTAGCTACAACGAACTTCAGA 3444 1182 GACCACUC G CUGUACAC 1045 GTGTACAG GGCTAGCTACAACGAGAGTGGTC 3445 1248 AUCAUUGU G CGGGUGGA 1048 TCCACCCG GGCTAGCTACAACGAACAATGAT 3446 1286 AAUGGACU G CAAGGAGU 1050 ACTCCTTG GGCTAGCTACAACGAAGTCCATT 3447 1344 CUUCGUUU G CCCAAGAA 1052 TTCTTGGG GGCTAGCTACAACGAAAACGAAG 3448 1366 UUGAAGCU G CAGUCAAA 1054 TTTGACTG GGCTAGCTACAACGAAGCTTCAA 3449 1442 GCUGGUGU G CUGGCAAG 1056 CTTGCCAG GGCTAGCTACAACGAACACCAGC 3450 1526 GUCCUUCC G CAUCACCA 1058 TGGTGATG GGCTAGCTACAACGAGGAAGGAC 3451 1542 AUCCUUCC G CAGCAAUA 1059 TATTGCTG GGCTAGCTACAACGAGGAAGGAT 3452 1554 CAAUACCU G CGGCCAGU 1060 ACTGGCCG GGCTAGCTACAACGAAGGTATTG 3453 1603 ACAAGUUU G CCAUCUCA 1062 TGAGATGG GGCTAGCTACAACGAAAACTTGT 3454 1699 UUGGCUUU G CUGUCAGC 1066 GCTGACAG GGCTAGCTACAACGAAAAGCCAA 3455 1708 CUGUCAGC G CUUGCCAU 1067 ATGGCAAG GGCTAGCTACAACGAGCTGACAG 3456 1712 CAGCGCUU G CCAUGUGC 1068 GCACATGG GGCTAGCTACAACGAAAGCGCTG 3457 1719 UGCCAUGU G CACGAUGA 1069 TCATCGTG GGCTAGCTACAACGAACATGGCA 3458 1843 UCAUGGCU G CCAUCUGU 1074 GCAGATGG GGCTAGCTACAACGAAGCCATGA 3459 1850 UGCCAUCU G CGCCCUCU 1075 AGAGGGCG GGCTAGCTACAACGAAGATGGCA 3460 1852 CCAUCUGC G CCCUCUUC 1076 GAAGAGGG GGCTAGCTACAACGAGCAGATGG 3461 1863 CUCUUCAU G CUGCCACU 1077 AGTGGCAG GGCTAGCTACAACGAATGAAGAG 3462 1866 UUCAUGCU G CCACUCUG 1078 CAGAGTGG GGCTAGCTACAACGAAGCATGAA 3463 1874 GCCACUCU G CCUCAUGG 1079 CCATGAGG GGCTAGCTACAACGAAGAGTGGC 3464 1895 UCAGUGGC G CUGCCUCC 1080 GGAGGCAG GGCTAGCTACAACGAGCCACTGA 3465 1898 GUGGCGCU G CCUCCGCU 1081 AGCGGAGG GGCTAGCTACAACGAAGCGCCAC 3466 1904 CUGCCUCC G CUGCCUGC 1082 GCAGGCAG GGCTAGCTACAACGAGGAGGCAG 3467 1907 CCUCCGCU G CCUGCGCC 1083 GGCGCAGG GGCTAGCTACAACGAAGCGGAGG 3468 1911 CGCUGCCU G CGCCAGCA 1084 TGCTGGCG GGCTAGCTACAACGAAGGCAGCG 3469 1913 CUGCCUGC G CCAGCAGC 1085 GCTGCTGG GGCTAGCTACAACGAGCAGGCAG 3470 1933 AUGACUUU G CUGAUGAC 1088 GTCATCAG GGCTAGCTACAACGAAAAGTCAT 3471 1950 AUCUCCCU G CUGAAGUG 1091 CACTTCAG GGCTAGCTACAACGAAGGGAGAT 3472 2087 CACCAAAU G CCUCUGCC 1094 GGCAGAGG GGCTAGCTACAACGAATTTGGTG 3473 2093 AUGCCUCU G CCUUGAUG 1095 CATCAAGG GGCTAGCTACAACGAAGAGGCAT 3474 2179 AGCACUCU G CUGGCGGG 1097 CCCGCCAG GGCTAGCTACAACGAAGAGTGCT 3475 2227 GAAAUUCU G CUGCUUGA 1098 TCAAGCAG GGCTAGCTACAACGAAGAATTTC 3476 2230 AUUCUGCU G CUUGAAAC 1099 GTTTCAAG GGCTAGCTACAACGAAGCAGAAT 3477 2329 CAUCACAC G CAGGUUAC 1102 GTAACCTG GGCTAGCTACAACGAGTGTGATG 3478 2393 GUUUCCCU G CUGGCCAA 1103 TTGGCCAG GGCTAGCTACAACGAAGGGAAAC 3479 2419 GAGAGGAU G CACAGUUU 1104 AAACTGTG GGCTAGCTACAACGAATCCTCTC 3480 2428 CACAGUUU G CUAUUUGC 1105 GCAAATAG GGCTAGCTACAACGAAAACTGTG 3481 2435 UGCUAUUU G CUUUAGAG 1106 CTCTAAAG GGCTAGCTACAACGAAAATAGCA 3482 2476 ACAUUGGU G CAAAGAUU 1107 AATCTTTG GGCTAGCTACAACGAACCAATGT 3483 2485 CAAAGAUU G CCUCUUGA 1108 TCAAGAGG GGCTAGCTACAACGAAATCTTTG 3484 219 GUGCCGAU G UAGCGGGC 1110 GCCCGCTA GGCTAGCTACAACGAATCGGCAC 3485 483 CUCCUGCU G UGGAUGGG 1111 CCCATCCA GGCTAGCTACAACGAAGCAGGAG 3486 634 GCAGCUUU G UGGAGAUG 1112 CATCTCCA GGCTAGCTACAACGAAAAGCTGC 3487 804 AGGCAGCU G UCCAGCAC 1113 GTGCTGGA GGCTAGCTACAACGAAGCTGCCT 3488 835 GGAAGGGU G UGUAUGUG 1114 CACATACA GGCTAGCTACAACGAACCCTTCC 3489 837 AAGGGUGU G UAUGUGCC 1115 GGCACATA GGCTAGCTACAACGAACACCCTT 3490 841 GUGUGUAU G UGCCCUAC 1116 GTAGGGCA GGCTAGCTACAACGAATACACAC 3491 919 ACGUCACU G UGCGUGCC 1117 GGCACGCA GGCTAGCTACAACGAAGTCACGT 3492 1100 GCAGCUUU G UGGUGCUG 1118 CAGCACCA GGCTAGCTACAACGAAAAGCTGC 3493 1144 UGGCCUCU G UCGGAGGG 1119 CCCTCCGA GGCTAGCTACAACGAAGAGGCCA 3494 1185 CACUCGCU G UACACAGG 1120 CCTGTGTA GGCTAGCTACAACGAAGCGAGTG 3495 1246 UGAUCAUU G UGCGGGUG 1121 CACCCGCA GGCTAGCTACAACGAAATGATCA 3496 1315 AGAGCAUU G UGGACAGU 1122 ACTGTCCA GGCTAGCTACAACGAAATGCTCT 3497 1356 AAGAAAGU G UUUGAAGC 1123 GCTTCAAA GGCTAGCTACAACGAACTTTCTT 3498 1440 CAGCUGGU G UGCUGGCA 1124 TGCCAGCA GGCTAGCTACAACGAACCAGCTG 3499 1570 UGGAAGAU G UGGCCACG 1125 CGTGGCCA GGCTAGCTACAACGAATCTTCCA 3500 1592 AGACGACU G UUACAAGU 1126 ACTTGTAA GGCTAGCTACAACGAAGTCGTCT 3501 1630 CGGGCACU G UUAUGGGA 1127 TCCCATAA GGCTAGCTACAACGAAGTGCCCG 3502 1642 UGGGAGCU G UUAUCAUG 1128 CATGATAA GGCTAGCTACAACGAAGCTCCCA 3503 1666 UCUACGUU G UCUUUGAU 1129 ATCAAAGA GGCTAGCTACAACGAAACGTAGA 3504 1702 GCUUUGCU G UCAGCGCU 1130 AGCGCTGA GGCTAGCTACAACGAAGCAAAGC 3505 1717 CUUGCCAU G UGCACGAU 1131 ATCGTGCA GGCTAGCTACAACGAATGGCAAG 3506 1759 GCCCUUUU G UCACCUUG 1132 CAAGGTGA GGCTAGCTACAACGAAAAAGGGC 3507 1781 GGAAGACU G UGGCUACA 1133 TGTAGCCA GGCTAGCTACAACGAAGTCTTCC 3508 1834 UAGCCUAU G UCAUGGCU 1134 AGCCATGA GGCTAGCTACAACGAATAGGCTA 3509 1884 CUCAUGGU G UGUCAGUG 1135 CACTGACA GGCTAGCTACAACGAACCATGAG 3510 1886 CAUGGUGU G UCAGUGGC 1136 GCCACTGA GGCTAGCTACAACGAACACCATG 3511 2048 UGGCACCU G UGGCCAGA 1137 TCTGGCCA GGCTAGCTACAACGAAGGTGCCA 3512 2139 CAGGGACU G UACCUGUA 1138 TACAGGTA GGCTAGCTACAACGAAGTCCCTG 3513 2145 CUGUACCU G UAGGAAAC 1139 GTTTCCTA GGCTAGCTACAACGAAGGTACAG 3514 2256 GAACCUUU G UCCACCAU 1140 ATGGTGGA GGCTAGCTACAACGAAAAGGTTC 3515 2346 CUUGGCGU G UGUCCCUG 1141 CAGGGACA GGCTAGCTACAACGAACGCCAAG 3516 2348 UGGCGUGU G UCCCUGUG 1142 CACAGGGA GGCTAGCTACAACGAACACGCCA 3517 2354 GUGUCCCU G UGGUACCC 1143 GGGTACCA GGCTAGCTACAACGAAGGGACAC 3518 2385 CCAAGCUU G UUUCCCUG 1144 CAGGGAAA GGCTAGCTACAACGAAAGCTTGG 3519 2453 CAGGGACU G UAUAAACA 1145 TGTTTATA GGCTAGCTACAACGAAGTCCCTG 3520 14 CGUCCGCA G CCCGCCCG 1146 CGGGCGGG GGCTAGCTACAACGATGCGGACG 3521 26 GCCCGGGA G CUGCGAGC 1147 GCTCGCAG GGCTAGCTACAACGATCCCGGGC 3522 33 AGCUGCGA G CCGCGAGC 1148 GCTCGCGG GGCTAGCTACAACGATCGCAGCT 3523 40 AGCCGCGA G CUGGAUUA 1149 TAATCCAG GGCTAGCTACAACGATCGCGGCT 3524 51 GGAUUAUG G UGGCCUGA 1150 TCAGGCCA GGCTAGCTACAACGACATAATCC 3525 54 UUAUGGUG G CCUGAGCA 1151 TGCTCAGG GGCTAGCTACAACGACACCATAA 3526 60 UGGCCUGA G CAGCCAAC 1152 GTTGGCTG GGCTAGCTACAACGATCAGGCCA 3527 63 CCUGAGCA G CCAACGCA 1153 TGCGTTGG GGCTAGCTACAACGATGCTCAGG 3528 72 CCAACGCA G CCGCAGGA 1154 TCCTGCGG GGCTAGCTACAACGATGCGTTGG 3529 81 CCGCAGGA G CCCGGAGC 1155 GCTCCGGG GGCTAGCTACAACGATCCTGCGG 3530 88 AGCCCGGA G CCCUUGCC 1156 GGCAAGGG GGCTAGCTACAACGATCCGGGCT 3531 134 CCAGGGAA G CCGCCACC 1157 GGTGGCGG GGCTAGCTACAACGATTCCCTGG 3532 144 CGCCACCG G CCCGCCAU 1158 ATGGCGGG GGCTAGCTACAACGACGGTGGCG 3533 167 CCCUCCCA G CCCCGCCG 1159 CGGCGGGG GGCTAGCTACAACGATGGGAGGG 3534 179 CGCCGGGA G CCCGCGCC 1160 GGCGCGGG GGCTAGCTACAACGATCCCGGCG 3535 198 CUGCCCAG G CUGGCCGC 1161 GCGGCCAG GGCTAGCTACAACGACTGGGCAG 3536 202 CCAGGCUG G CCGCCGCC 1162 GGCGGCGG GGCTAGCTACAACGACAGCCTGG 3537 211 CCGCCGCC G UGCCGAUG 1163 CATCGGCA GGCTAGCTACAACGAGGCGGCGG 3538 222 CCGAUGUA G CGGGCUCC 1164 GGAGCCCG GGCTAGCTACAACGATACATCGG 3539 226 UGUAGCGG G CUCCGGAU 1165 ATCCGGAG GGCTAGCTACAACGACCGCTACA 3540 239 GGAUCCCA G CCUCUCCC 1166 GGGAGAGG GGCTAGCTACAACGATGGGATCC 3541 256 CUGCUCCC G UGCUCUGC 1167 GCAGAGCA GGCTAGCTACAACGAGGGAGCAG 3542 290 UCUCCACA G CCCGGACC 1168 GGTCCGGG GGCTAGCTACAACGATGTGGAGA 3543 304 ACCCGGGG G CUGGCCCA 1169 TGGGCCAG GGCTAGCTACAACGACCCCGGGT 3544 308 GGGGGCUG G CCCAGGGC 1170 GCCCTGGG GGCTAGCTACAACGACAGCCCCC 3545 315 GGCCCAGG G CCCUGCAG 1171 CTGCAGGG GGCTAGCTACAACGACCTGGGCC 3546 324 CCCUGCAG G CCCUGGCG 1172 CGCCAGGG GGCTAGCTACAACGACTGCAGGG 3547 330 AGGCCCUG G CGUCCUGA 1173 TCAGGACG GGCTAGCTACAACGACAGGGCCT 3548 332 GCCCUGGC G UCCUGAUG 1174 CATCAGGA GGCTAGCTACAACGAGCCAGGGC 3549 348 GCCCCCAA G CUCCCUCU 1175 AGAGGGAG GGCTAGCTACAACGATTGGGGGC 3550 365 CCUGAGAA G CCACCAGC 1176 GCTGGTGG GGCTAGCTACAACGATTCTCAGG 3551 372 AGCCACCA G CACCACCC 1177 GGGTGGTG GGCTAGCTACAACGATGGTGGCT 3552 391 ACUUGGGG G CAGGCGCC 1178 GGCGCCTG GGCTAGCTACAACGACCCCAAGT 3553 395 GGGGGCAG G CGCCAGGG 1179 CCCTGGCG GGCTAGCTACAACGACTGCCCCC 3554 410 GGACGGAC G UGGGCCAG 1180 CTGGCCCA GGCTAGCTACAACGAGTCCGTCC 3555 414 GGACGUGG G CCAGUGCG 1181 CGCACTGG GGCTAGCTACAACGACCACGTCC 3556 418 GUGGGCCA G UGCGAGCC 1182 GGCTCGCA GGCTAGCTACAACGATGGCCCAC 3557 424 CAGUGCGA G CCCAGAGG 1183 CCTCTGGG GGCTAGCTACAACGATCGCACTG 3558 433 CCCAGAGG G CCCGAAGG 1184 CCTTCGGG GGCTAGCTACAACGACCTCTGGG 3559 441 GCCCGAAG G CCGGGGCC 1185 GGCCCCGG GGCTAGCTACAACGACTTCGGGC 3560 447 AGGCCGGG G CCCACCAU 1186 ATGGTGGG GGCTAGCTACAACGACCCGGCCT 3561 457 CCACCAUG G CCCAAGCC 1187 GGCTTGGG GGCTAGCTACAACGACATGGTGG 3562 463 UGGCCCAA G CCCUGCCC 1188 GGGCAGGG GGCTAGCTACAACGATTGGGCCA 3563 474 CUGCCCUG G CUCCUGCU 1189 AGCAGGAG GGCTAGCTACAACGACAGGGCAG 3564 491 GUGGAUGG G CGCGGGAG 1190 CTCCCGCG GGCTAGCTACAACGACCATCCAC 3565 499 GCGCGGGA G UGCUGCCU 1191 AGGCAGCA GGCTAGCTACAACGATCCCGCGC 3566 515 UGCCCACG G CACCCAGC 1192 GCTGGGTG GGCTAGCTACAACGACGTGGGCA 3567 522 GGCACCCA G CACGGCAU 1193 ATGCCGTG GGCTAGCTACAACGATGGGTGCC 3568 527 CCAGCACG G CAUCCGGC 1194 GCCGGATG GGCTAGCTACAACGACGTGCTGG 3569 534 GGCAUCCG G CUGCCCCU 1195 AGGGGCAG GGCTAGCTACAACGACGGATGCC 3570 548 CCUGCGCA G CGGCCUGG 1196 CCAGGCCG GGCTAGCTACAACGATGCGCAGG 3571 551 GCGCAGCG G CCUGGGGG 1197 CCCCCAGG GGCTAGCTACAACGACGCTGCGC 3572 560 CCUGGGGG G CGCCCCCC 1198 GGGGGGCG GGCTAGCTACAACGACCCCCAGG 3573 573 CCCCUGGG G CUGCGGCU 1199 AGCCGCAG GGCTAGCTACAACGACCCAGGGG 3574 579 GGGCUGCG G CUGCCCCG 1200 CGGGGCAG GGCTAGCTACAACGACGCAGCCC 3575 603 GACGAAGA G CCCGAGGA 1201 TCCTCGGG GGCTAGCTACAACGATCTTCGTC 3576 612 CCCGAGGA G CCCGGCCG 1202 CGGCCGGG GGCTAGCTACAACGATCCTCGGG 3577 617 GGAGCCCG G CCGGAGGG 1203 CCCTCCGG GGCTAGCTACAACGACGGGCTCC 3578 626 CCGGAGGG G CAGCUUUG 1204 CAAAGCTG GGCTAGCTACAACGACCCTCCGG 3579 629 GAGGGGCA G CUUUGUGG 1205 CCACAAAG GGCTAGCTACAACGATGCCCCTC 3580 643 UGGAGAUG G UGGACAAC 1206 GTTGTCCA GGCTAGCTACAACGACATCTCCA 3581 659 CCUGAGGG G CAAGUCGG 1207 CCGACTTG GGCTAGCTACAACGACCCTCAGG 3582 663 AGGGGCAA G UCGGGGCA 1208 TGCCCCGA GGCTAGCTACAACGATTGCCCCT 3583 669 AAGUCGGG G CAGGGCUA 1209 TAGCCCTG GGCTAGCTACAACGACCCGACTT 3584 674 GGGGCAGG G CUACUACG 1210 CGTAGTAG GGCTAGCTACAACGACCTGCCCC 3585 682 GCUACUAC G UGGAGAUG 1211 CATCTCCA GGCTAGCTACAACGAGTAGTAGC 3586 694 AGAUGACC G UGGGCAGC 1212 GCTGCCCA GGCTAGCTACAACGAGGTCATCT 3587 698 GACCGUGG G CAGCCCCC 1213 GGGGGCTG GGCTAGCTACAACGACCACGGTC 3588 701 CGUGGGCA G CCCCCCGC 1214 GCGGGGGG GGCTAGCTACAACGATGCCCACG 3589 727 ACAUCCUG G UGGAUACA 1215 TGTATCCA GGCTAGCTACAACGACAGGATGT 3590 737 GGAUACAG G CAGCAGUA 1216 TACTGCTG GGCTAGCTACAACGACTGTATCC 3591 740 UACAGGCA G CAGUAACU 1217 AGTTACTG GGCTAGCTACAACGATGCCTGTA 3592 743 AGGCAGCA G UAACUUUG 1218 CAAAGTTA GGCTAGCTACAACGATGCTGCCT 3593 754 ACUUUGCA G UGGGUGCU 1219 AGCACCCA GGCTAGCTACAACGATGCAAAGT 3594 758 UGCAGUGG G UGCUGCCC 1220 GGGCAGCA GGCTAGCTACAACGACCACTGCA 3595 798 UACCAGAG G CAGCUGUC 1221 GACAGCTG GGCTAGCTACAACGACTCTGGTA 3596 801 CAGAGGCA G CUGUCCAG 1222 CTGGACAG GGCTAGCTACAACGATGCCTCTG 3597 809 GCUGUCCA G CACAUACC 1223 GGTATGTG GGCTAGCTACAACGATGGACAGC 3598 833 CCGGAAGG G UGUGUAUG 1224 CATACACA GGCTAGCTACAACGACCTTCCGG 3599 857 CACCCAGG G CAAGUGGG 1225 CCCACTTG GGCTAGCTACAACGACCTGGGTG 3600 861 CAGGGCAA G UGGGAAGG 1226 CCTTCCCA GGCTAGCTACAACGATTGCCCTG 3601 873 GAAGGGGA G CUGGGCAC 1227 GTGCCCAG GGCTAGCTACAACGATCCCCTTC 3602 878 GGAGCUGG G CACCGACC 1228 GGTCGGTG GGCTAGCTACAACGACCAGCTCC 3603 889 CCGACCUG G UAAGCAUG 1229 GATGCTTA GGCTAGCTACAACGACAGGTCGG 3604 893 CCUGGUAA G CAUCCCCC 1230 GGGGGATG GGCTAGCTACAACGATTACCAGG 3605 905 CCCCCAUG G CCCCAACG 1231 CGTTGGGG GGCTAGCTACAACGACATGGGGG 3606 913 GCCCCAAC G UCACUGUG 1232 CACAGTGA GGCTAGCTACAACGAGTTGGGGC 3607 923 CACUGUGC G UGCCAACA 1233 TGTTGGCA GGCTAGCTACAACGAGCACAGTG 3608 957 UCAGACAA G UUCUUCAU 1234 ATGAAGAA GGCTAGCTACAACGATTGTCTGA 3609 971 CAUCAACG G CUCCAACU 1235 AGTTGGAG GGCTAGCTACAACGACGTTGATG 3610 986 CUGGGAAG G CAUCCUGG 1236 CCAGGATG GGCTAGCTACAACGACTTCCCAG 3611 996 AUCCUGGG G CUGGCCUA 1237 TAGGCCAG GGCTAGCTACAACGACCCAGGAT 3612 1000 UGGGGCUG G CCUAUGCU 1238 AGCATAGG GGCTAGCTACAACGACAGCCCCA 3613 1020 AUUGCCAG G CCUGACGA 1239 TCGTCAGG GGCTAGCTACAACGACTGGCAAT 3614 1038 UCCCUGGA G CCUUUCUU 1240 AAGAAAGG GGCTAGCTACAACGATCCAGGGA 3615 1057 ACUCUCUG G UAAAGCAG 1241 CTGCTTTA GGCTAGCTACAACGACAGAGAGT 3616 1062 CUGGUAAA G CAGACCCA 1242 TGGGTCTG GGCTAGCTACAACGATTTACCAG 3617 1072 AGACCCAC G UUCCCAAC 1243 GTTGGGAA GGCTAGCTACAACGAGTGGGTCT 3618 1095 UCCCUGCA G CUUUGUGG 1244 CCACAAAG GGCTAGCTACAACGATGCAGGGA 3619 1103 GCUUUGUG G UGCUGGCU 1245 AGCCAGCA GGCTAGCTACAACGACACAAAGC 3620 1109 UGGUGCUG G CUUCCCCC 1246 GGGGGAAG GGCTAGCTACAACGACAGCACCA 3621 1125 CUCAACCA G UCUGAAGU 1247 ACTTCAGA GGCTAGCTACAACGATGGTTGAG 3622 1132 AGUCUGAA G UGCUGGCC 1248 GGCCAGCA GGCTAGCTACAACGATTCAGACT 3623 1138 AAGUGCUG G CCUCUGUC 1249 GACAGAGG GGCTAGCTACAACGACAGCACTT 3624 1154 CGGAGGGA G CAUGAUCA 1250 TGATCATG GGCTAGCTACAACGATCCCTCCG 3625 1169 CAUUGGAG G UAUCGACC 1251 GGTCGATA GGCTAGCTACAACGACTCCAATG 3626 1193 GUACACAG G CAGUCUCU 1252 AGAGACTG GGCTAGCTACAACGACTGTGTAC 3627 1196 CACAGGCA G UCUCUGGU 1253 ACCAGAGA GGCTAGCTACAACGATGCCTGTG 3628 1203 AGUCUCUG G UAUACACC 1254 GGTGTATA GGCTAGCTACAACGACAGAGACT 3629 1218 CCCAUCCG G CGGGAGUG 1255 CACTCCCG GGCTAGCTACAACGACGGATGGG 3630 1224 CGGCGGGA G UGGUAUUA 1256 TAATACCA GGCTAGCTACAACGATCCCGCCG 3631 1227 CGGGAGUG G UAUUAUGA 1257 TCATAATA GGCTAGCTACAACGACACTCCCG 3632 1237 AUUAUGAG G UGAUCAUU 1258 AATGATCA GGCTAGCTACAACGACTCATAAT 3633 1252 UUGUGCGG G UGGAGAUC 1259 GATCTCCA GGCTAGCTACAACGACCGCACAA 3634 1293 UGCAAGGA G UACAACUA 1260 TAGTTGTA GGCTAGCTACAACGATCCTTGCA 3635 1310 UGACAAGA G CAUUGUGG 1261 CCACAATG GGCTAGCTACAACGATCTTGTCA 3636 1322 UGUGGACA G UGGCACCA 1262 TGGTGCCA GGCTAGCTACAACGATGTCCACA 3637 1325 GGACAGUG G CACCACCA 1263 TGGTGGTG GGCTAGCTACAACGACACTGTCC 3638 1340 CAACCUUC G UUUGCCCA 1264 TGGGCAAA GGCTAGCTACAACGAGAAGGTTG 3639 1354 CCAAGAAA G UGUUUGAA 1265 TTCAAACA GGCTAGCTACAACGATTTCTTGG 3640 1363 UGUUUGAA G CUGCAGUC 1266 GACTGCAG GGCTAGCTACAACGATTCAAACA 3641 1369 AAGCUGCA G UCAAAUCC 1267 GGATTTGA GGCTAGCTACAACGATGCAGCTT 3642 1384 CCAUCAAG G CAGCCUCC 1268 GGAGGCTG GGCTAGCTACAACGACTTGATGG 3643 1387 UCAAGGCA G CCUCCUCC 1269 GGAGGAGG GGCTAGCTACAACGATGCCTTGA 3644 1404 ACGGAGAA G UUCCCUGA 1270 TCAGGGAA GGCTAGCTACAACGATTCTCCGT 3645 1415 CCCUGAUG G UUUCUGGC 1271 GCCAGAAA GGCTAGCTACAACGACATCAGGG 3646 1422 GGUUUCUG G CUAGGAGA 1272 TCTCCTAG GGCTAGCTACAACGACAGAAACC 3647 1431 CUAGGAGA G CAGCUGGU 1273 ACCAGCTG GGCTAGCTACAACGATCTCCTAG 3648 1434 GGAGAGCA G CUGGUGUG 1274 CACACCAG GGCTAGCTACAACGATGCTCTCC 3649 1438 AGCAGCUG G UGUGCUGG 1275 CCAGCACA GGCTAGCTACAACGACAGCTGCT 3650 1446 GUGUGCUG G CAAGCAGG 1276 CCTGCTTG GGCTAGCTACAACGACAGCACAC 3651 1450 GCUGGCAA G CAGGCACC 1277 GGTGCCTG GGCTAGCTACAACGATTGCCAGC 3652 1454 GCAAGCAG G CACCACCC 1278 GGGTGGTG GGCTAGCTACAACGACTGCTTGC 3653 1480 UUUUCCCA G UCAUCUCA 1279 TGAGATGA GGCTAGCTACAACGATGGGAAAA 3654 1502 CCUAAUGG G UGAGGUUA 1280 TAACCTCA GGCTAGCTACAACGACCATTAGG 3655 1507 UGGGUGAG G UUACCAAC 1281 GTTGGTAA GGCTAGCTACAACGACTCACCCA 3656 1518 ACCAACCA G UCCUUCCG 1282 CGGAAGGA GGCTAGCTACAACGATGGTTGGT 3657 1545 CUUCCGCA G CAAUACCU 1283 AGGTATTG GGCTAGCTACAACGATGCGGAAG 3658 1557 UACCUGCG G CCAGUGGA 1284 TCCACTGG GGCTAGCTACAACGACGCAGGTA 3659 1561 UGCGGCCA G UGGAAGAU 1285 ATCTTCCA GGCTAGCTACAACGATGGCCGCA 3660 1573 AAGAUGUG G CCACGUCC 1286 GGACGTGG GGCTAGCTACAACGACACATCTT 3661 1578 GUGGCCAC G UCCCAAGA 1287 TCTTGGGA GGCTAGCTACAACGAGTGGCCAC 3662 1599 UGUUACAA G UUUGCCAU 1288 ATGGCAAA GGCTAGCTACAACGATTGTAACA 3663 1614 AUCUCACA G UCAUCCAC 1289 GTGGATGA GGCTAGCTACAACGATGTGAGAT 3664 1625 AUCCACGG G CACUGUUA 1290 TAACAGTG GGCTAGCTACAACGACCGTGGAT 3665 1639 UUAUGGGA G CUGUUAUC 1291 GATAACAG GGCTAGCTACAACGATCCCATAA 3666 1655 CAUGGAGG G CUUCUACG 1292 CGTAGAAG GGCTAGCTACAACGACCTCCATG 3667 1663 GCUUCUAC G UUGUCUUU 1293 AAAGACAA GGCTAGCTACAACGAGTAGAAGC 3668 1678 UUGAUCGG G CCCGAAAA 1294 TTTTCGGG GGCTAGCTACAACGACCGATCAA 3669 1694 ACGAAUUG G CUUUGCUG 1295 CAGCAAAG GGCTAGCTACAACGACAATTCGT 3670 1706 UGCUGUCA G CGCUUGCC 1296 GGCAAGCG GGCTAGCTACAACGATGACAGCA 3671 1728 CACGAUGA G UUCAGGAC 1297 GTCCTGAA GGCTAGCTACAACGATCATCGTG 3672 1738 UCAGGACG G CAGCGGUG 1298 CACCGCTG GGCTAGCTACAACGACGTCCTGA 3673 1741 GGACGGCA G CGGUGGAA 1299 TTCCACCG GGCTAGCTACAACGATGCCGTCC 3674 1744 CGGCAGCG G UGGAAGGC 1300 GCCTTCCA GGCTAGCTACAACGACGCTGCCG 3675 1751 GGUGGAAG G CCCUUUUG 1301 CAAAAGGG GGCTAGCTACAACGACTTCCACC 3676 1784 AGACUGUG G CUACAACA 1302 TGTTGTAG GGCTAGCTACAACGACACAGTCT 3677 1809 ACAGAUGA G UCAACCCU 1303 AGGGTTGA GGCTAGCTACAACGATCATCTGT 3678 1828 UGACCAUA G CCUAUGUC 1304 GACATAGG GGCTAGCTACAACGATATGGTCA 3679 1840 AUGUCAUG G CUGCCAUC 1305 GATGGCAG GGCTAGCTACAACGACATGACAT 3680 1882 GCCUCAUG G UGUGUCAG 1306 CTGACACA GGCTAGCTACAACGACATGAGGC 3681 1890 GUGUGUCA G UGGCGCUG 1307 CAGCGCCA GGCTAGCTACAACGATGACACAC 3682 1893 UGUCAGUG G CGCUGCCU 1308 AGGCAGCG GGCTAGCTACAACGACACTGACA 3683 1917 CUGCGCCA G CAGCAUGA 1309 TCATGCTG GGCTAGCTACAACGATGGCGCAG 3684 1920 CGCCAGCA G CAUGAUGA 1310 TCATCATG GGCTAGCTACAACGATGCTGGCG 3685 1956 CUGCUGAA G UGAGGAGG 1311 CCTCCTCA GGCTAGCTACAACGATTCAGCAG 3686 1964 GUGAGGAG G CCCAUGGG 1312 CCCATGGG GGCTAGCTACAACGACTCCTCAC 3687 1972 GCCCAUGG G CAGAAGAU 1313 ATCTTCTG GGCTAGCTACAACGACCATGGGC 3688 2006 ACACCUCC G UGGUUCAC 1314 GTGAACCA GGCTAGCTACAACGAGGAGGTGT 3689 2009 CCUCCGUG G UUCACUUU 1315 AAAGTGAA GGCTAGCTACAACGACACGGAGG 3690 2019 UCACUUUG G UCACAAGU 1316 ACTTGTGA GGCTAGCTACAACGACAAAGTGA 3691 2026 GGUCACAA G UAGGAGAC 1317 GTCTCCTA GGCTAGCTACAACGATTGTGACC 3692 2042 CACAGAUG G CACCUGUG 1318 CACAGGTG GGCTAGCTACAACGACATCTGTG 3693 2051 CACCUGUG G CCAGAGCA 1319 TGCTCTGG GGCTAGCTACAACGACACAGGTG 3694 2057 UGGCCAGA G CACCUCAG 1320 CTGAGGTG GGCTAGCTACAACGATCTGGCCA 3695 2114 AGGAAAAG G CUGGCAAG 1321 CTTGCCAG GGCTAGCTACAACGACTTTTCCT 3696 2118 AAAGGCUG G CAAGGUGG 1322 CCACCTTG GGCTAGCTACAACGACAGCCTTT 3697 2123 CUGGCAAG G UGGGUUCC 1323 GGAACCCA GGCTAGCTACAACGACTTGCCAG 3698 2127 CAAGGUGG G UUCCAGGG 1324 CCCTGGAA GGCTAGCTACAACGACCACCTTG 3699 2172 AGAAAGAA G CACUCUGC 1325 GCAGAGTG GGCTAGCTACAACGATTCTTTCT 3700 2183 CUCUGCUG G CGGGAAUA 1326 TATTCCCG GGCTAGCTACAACGACAGCAGAG 3701 2198 UACUCUUG G UCACCUCA 1327 TGAGGTGA GGCTAGCTACAACGACAAGAGTA 3702 2214 AAAUUUAA G UCGGGAAA 1328 TTTCCCGA GGCTAGCTACAACGATTAAATTT 3703 2243 AAACUUCA G CCCUGAAC 1329 GTTCAGGG GGCTAGCTACAACGATGAAGTTT 3704 2288 AACCCAAA G UAUUCUUC 1330 GAAGAATA GGCTAGCTACAACGATTTGGGTT 3705 2305 UUUUCUUA G UUUCAGAA 1331 TTCTGAAA GGCTAGCTACAACGATAAGAAAA 3706 2314 UUUCAGAA G UACUGGCA 1332 TGCCAGTA GGCTAGCTACAACGATTCTGAAA 3707 2320 AAGUACUG G CAUCACAC 1333 GTGTGATG GGCTAGCTACAACGACAGTACTT 3708 2333 ACACGCAG G UUACCUUG 1334 CAAGGTAA GGCTAGCTACAACGACTGCGTGT 3709 2342 UUACCUUG G CGUGUGUC 1335 GACACACG GGCTAGCTACAACGACAAGGTAA 3710 2344 ACCUUGGC G UGUGUCCC 1336 GGGACACA GGCTAGCTACAACGAGCCAAGGT 3711 2357 UCCCUGUG G UACCCUGG 1337 CCAGGGTA GGCTAGCTACAACGACACAGGGA 3712 2365 GUACCCUG G CAGAGAAG 1338 CTTCTCTG GGCTAGCTACAACGACAGGGTAC 3713 2381 GAGACCAA G CUUGUUUC 1339 GAAACAAG GGCTAGCTACAACGATTGGTCTC 3714 2397 CCCUGCUG G CCAAAGUC 1340 GACTTTGG GGCTAGCTACAACGACAGCAGGG 3715 2403 UGGCCAAA G UCAGUAGG 1341 CCTACTGA GGCTAGCTACAACGATTTGGCCA 3716 2407 CAAAGUCA G UAGGAGAG 1342 CTCTCCTA GGCTAGCTACAACGATGACTTTG 3717 2424 GAUGCACA G UUUGCUAU 1343 ATAGCAAA GGCTAGCTACAACGATGTGCATC 3718 2463 AUAAACAA G CCUAACAU 1344 ATGTTAGG GGCTAGCTACAACGATTGTTTAT 3719 2474 UAACAUUG G UGCAAAGA 1345 TCTTTGCA GGCTAGCTACAACGACAATGTTA 3720 45 CGAGCUGG A UCAUGGUG 1346 CACCATAA GGCTAGCTACAACGACCAGCTCG 3721 67 AGCAGCCA A CGCAGCCG 1347 CGGCTGCG GGCTAGCTACAACGATGGCTGCT 3722 125 CCGGGGGG A CCAGGGAA 1348 TTCCCTGG GGCTAGCTACAACGACCCCCCGG 3723 217 CCGUGCCG A UGUAGCGG 1349 CCGCTACA GGCTAGCTACAACGACGGCACGG 3724 233 GGCUCCGG A UCCCAGCC 1350 GGCTGGGA GGCTAGCTACAACGACCGGAGCC 3725 267 CUCUGCGG A UCUCCCCU 1351 AGGGCAGA GGCTAGCTACAACGACCGCAGAG 3726 277 CUCCCCUG A CCGCUCUC 1352 GAGAGCGG GGCTAGCTACAACGACAGGGGAG 3727 296 CAGCCCGG A CCCGGGGG 1353 CCCCCGGG GGCTAGCTACAACGACCGGGCTG 3728 338 GCGUCCUG A UGCCCCCA 1354 TGGGGGCA GGCTAGCTACAACGACAGGACGC 3729 383 CCACCCAG A CUUGGGGG 1355 CCCCCAAG GGCTAGCTACAACGACTGGGTGG 3730 404 CGCCAGGG A CGGACGUG 1356 CACGTCCG GGCTAGCTACAACGACCCTGGCG 3731 408 AGGGACGG A CGUGGGCC 1357 GGCCCACG GGCTAGCTACAACGACCGTCCCT 3732 487 UGCUGUGG A UGGGCGCG 1358 CGCGCCCA GGCTAGCTACAACGACCACAGCA 3733 592 CCCGGGAG A CCGACGAA 1359 TTCGTCGG GGCTAGCTACAACGACTCCCGGG 3734 596 GGAGACCG A CGAAGAGC 1360 GCTCTTCG GGCTAGCTACAACGACGGTCTCC 3735 640 UUGUGGAG A UGGUGGAC 1361 GTCCACCA GGCTAGCTACAACGACTCCACAA 3736 647 GAUGGUGG A CAACCUGA 1362 TCAGGTTG GGCTAGCTACAACGACCACCATC 3737 650 GGUGGACA A CCUGAGGG 1363 CCCTCAGG GGCTAGCTACAACGATGTCCACC 3738 688 ACGUGGAG A UGACCGUG 1364 CACGGTCA GGCTAGCTACAACGACTCCACGT 3739 691 UGGAGAUG A CCGUGGGC 1365 GCCCACGG GGCTAGCTACAACGACATCTCCA 3740 712 CCCCGCAG A CGCUCAAC 1366 GTTGAGCG GGCTAGCTACAACGACTGCGGGG 3741 719 GACGCUCA A CAUCCUGG 1367 CCAGGATG GGCTAGCTACAACGATGAGCGTC 3742 731 CCUGGUGG A UACAGGCA 1368 TGCCTGTA GGCTAGCTACAACGACCACCAGG 3743 746 CAGCAGUA A CUUUGCAG 1369 CTGCAAAG GGCTAGCTACAACGATACTGCTG 3744 821 AUACCGGG A CCUCCGGA 1370 TCCGGAGG GGCTAGCTACAACGACCCGGTAT 3745 884 GGGCACCG A CCUGGUAA 1371 TTACCAGG GGCTAGCTACAACGACGGTGCCC 3746 911 UGGCCCCA A CGUCACUG 1372 CAGTGACG GGCTAGCTACAACGATGGGGCCA 3747 929 GCGUGCCA A CAUUGCUG 1373 CAGCAATG GGCTAGCTACAACGATGGCACGC 3748 948 AUCACUGA A UCAGACAA 1374 TTGTCTGA GGCTAGCTACAACGATCAGTGAT 3749 953 UGAAUCAG A CAAGUUCU 1375 AGAACTTG GGCTAGCTACAACGACTGATTCA 3750 968 CUUCAUCA A CGGCUCCA 1376 TGGAGCCG GGCTAGCTACAACGATGATGAAG 3751 977 CGGCUCCA A CUGGGAAG 1377 CTTCCCAG GGCTAGCTACAACGATGGAGCCG 3752 1012 AUGCUGAG A UUGCCAGG 1378 CCTGGCAA GGCTAGCTACAACGACTCAGCAT 3753 1025 CAGGCCUG A CGACUCCC 1379 GGGAGTCG GGCTAGCTACAACGACAGGCCTG 3754 1028 GCCUGACG A CUCCCUGG 1380 CCAGGGAG GGCTAGCTACAACGACGTCAGGC 3755 1049 UUUCUUUG A CUCUCUGG 1381 CCAGAGAG GGCTAGCTACAACGACAAAGAAA 3756 1066 UAAAGCAG A CCCACGUU 1382 AACGTGGG GGCTAGCTACAACGACTGCTTTA 3757 1079 CGUUCCCA A CCUCUUCU 1383 AGAAGAGG GGCTAGCTACAACGATGGGAACG 3758 1121 CCCCCUCA A CCAGUCUG 1384 CAGACTGG GGCTAGCTACAACGATGAGGGGG 3759 1159 GGAGCAUG A UCAUUGGA 1385 TCCAATGA GGCTAGCTACAACGACATGCTCC 3760 1175 AGGUAUCG A CCACUCGC 1386 GCGAGTGG GGCTAGCTACAACGACGATACCT 3761 1240 AUGAGGUG A UCAUUGUG 1387 CACAATGA GGCTAGCTACAACGACACCTCAT 3762 1258 GGGUGGAG A UCAAUGGA 1388 TCCATTGA GGCTAGCTACAACGACTCCACCC 3763 1262 GGAGAUCA A UGGACAGG 1389 CCTGTCCA GGCTAGCTACAACGATGATCTCC 3764 1266 AUCAAUGG A CAGGAUCU 1390 AGATCCTG GGCTAGCTACAACGACCATTGAT 3765 1271 UGGACAGG A UCUGAAAA 1391 TTTTCAGA GGCTAGCTACAACGACCTGTCCA 3766 1279 AUCUGAAA A UGGACUGC 1392 GCAGTCCA GGCTAGCTACAACGATTTCAGAT 3767 1283 GAAAAUGG A CUGCAAGG 1393 CCTTGCAG GGCTAGCTACAACGACCATTTTC 3768 1298 GGAGUACA A CUAUGACA 1394 TGTCATAG GGCTAGCTACAACGATGTACTCC 3769 1304 CAACUAUG A CAAGAGCA 1395 TGCTCTTG GGCTAGCTACAACGACATAGTTG 3770 1319 CAUUGUGG A CAGUGGCA 1396 TGCCACTG GGCTAGCTACAACGACCACAATG 3771 1334 CACCACCA A CCUUCGUU 1397 AACGAAGG GGCTAGCTACAACGATGGTGGTG 3772 1374 GCAGUCAA A UCCAUCAA 1398 TTGATGGA GGCTAGCTACAACGATTGACTGC 3773 1412 GUUCCCUG A UGGUUUCU 1399 AGAAACCA GGCTAGCTACAACGACAGGGAAC 3774 1469 CCCUUGGA A CAUUUUCC 1400 GGAAAATG GGCTAGCTACAACGATCCAAGGG 3775 1498 UCUACCUA A UGGGUGAG 1401 CTCACCCA GGCTAGCTACAACGATAGGTAGA 3776 1514 GGUUACCA A CCAGUCCU 1402 AGGACTGG GGCTAGCTACAACGATGGTAACC 3777 1548 CCGCAGCA A UACCUGCG 1403 CGCAGGTA GGCTAGCTACAACGATGCTGCGG 3778 1568 AGUGGAAG A UGUGGCCA 1404 TGGCCACA GGCTAGCTACAACGACTTCCACT 3779 1586 GUCCCAAG A CGACUGUU 1405 AACAGTCG GGCTAGCTACAACGACTTGGGAC 3780 1589 CCAAGACG A CUGUUACA 1406 TGTAACAG GGCTAGCTACAACGACGTCTTGG 3781 1673 UGUCUUUG A UCGGGCCC 1407 GGGCCCGA GGCTAGCTACAACGACAAAGACA 3782 1686 GCCCGAAA A CGAAUUGG 1408 CCAATTCG GGCTAGCTACAACGATTTCGGGC 3783 1690 GAAAACGA A UUGGCUUU 1409 AAAGCCAA GGCTAGCTACAACGATCGTTTTC 3784 1724 UGUGCACG A UGAGUUCA 1410 TGAACTCA GGCTAGCTACAACGACGTGCACA 3785 1735 AGUUCAGG A CGGCAGCG 1411 CGCTGCCG GGCTAGCTACAACGACCTGAACT 3786 1769 CACCUUGG A CAUGGAAG 1412 CTTCCATG GGCTAGCTACAACGACCAAGGTG 3787 1778 CAUGGAAG A CUGUGGCU 1413 AGCCACAG GGCTAGCTACAACGACTTCCATG 3788 1790 UGGCUACA A CAUUCCAC 1414 GTGGAATG GGCTAGCTACAACGATGTAGCCA 3789 1801 UUCCACAG A CAGAUGAG 1415 CTCATCTG GGCTAGCTACAACGACTGTGGAA 3790 1805 ACAGACAG A UGAGUCAA 1416 TTGACTCA GGCTAGCTACAACGACTGTCTGT 3791 1813 AUGAGUCA A CCCUCAUG 1417 CATGAGGG GGCTAGCTACAACGATGACTCAT 3792 1822 CCCUCAUG A CCAUAGCC 1418 GGCTATGG GGCTAGCTACAACGACATGAGGG 3793 1925 GCAGCAUG A UGACUUUG 1419 CAAAGTCA GGCTAGCTACAACGACATGCTGC 3794 1928 GCAUGAUG A CUUUGCUG 1420 CAGCAAAG GGCTAGCTACAACGACATCATGC 3795 1937 CUUUGCUG A UGACAUCU 1421 AGATGTCA GGCTAGCTACAACGACAGCAAAG 3796 1940 UGCUGAUG A CAUCUCCC 1422 GGGAGATG GGCTAGCTACAACGACATCAGCA 3797 1979 GGCAGAAG A UAGAGAUU 1423 AATCTCTA GGCTAGCTACAACGACTTCTGCC 3798 1985 AGAUAGAG A UUCCCCUG 1424 CAGGGGAA GGCTAGCTACAACGACTCTATCT 3799 1995 UCCCCUGG A CCACACCU 1425 AGGTGTGG GGCTAGCTACAACGACCAGGGGA 3800 2033 AGUAGGAG A CACAGAUG 1426 CATCTGTG GGCTAGCTACAACGACTCCTACT 3801 2039 AGACACAG A UGGCACCU 1427 AGGTGCCA GGCTAGCTACAACGACTGTGTCT 3802 2067 ACCUCAGG A CCCUCCCC 1428 GGGGAGGG GGCTAGCTACAACGACCTGAGGT 3803 2085 CCCACCAA A UGCCUCUG 1429 CAGAGGCA GGCTAGCTACAACGATTGGTGGG 3804 2099 CUGCCUUG A UGGAGAAG 1430 CTTCTCCA GGCTAGCTACAACGACAAGGCAG 3805 2136 UUCCAGGG A CUGUACCU 1431 AGGTACAG GGCTAGCTACAACGACCCTGGAA 3806 2152 UGUAGGAA A CAGAAAAG 1432 CTTTTCTG GGCTAGCTACAACGATTCCTACA 3807 2189 UGGCGGGA A UACUCUUG 1433 CAAGAGTA GGCTAGCTACAACGATCCCGCCA 3808 2208 CACCUCAA A UUUAAGUC 1434 GACTTAAA GGCTAGCTACAACGATTGAGGTG 3809 2222 GUCGGGAA A UUCUCCUG 1435 CAGCAGAA GGCTAGCTACAACGATTCCCGAC 3810 2237 UGCUUGAA A CUUCAGCC 1436 GGCTGAAG GGCTAGCTACAACGATTCAAGCA 3811 2250 AGCCCUGA A CCUUUGUC 1437 GACAAAGG GGCTAGCTACAACGATCAGGGCT 3812 2273 UCCUUUAA A UUCUCCAA 1438 TTGGAGAA GGCTAGCTACAACGATTAAAGGA 3813 2281 AUUCUCCA A CCCAAAGU 1439 ACTTTGGG GGCTAGCTACAACGATGGAGAAT 3814 2376 GAGAAGAG A CCAAGCUU 1440 AAGCTTGG GGCTAGCTACAACGACTCTTCTC 3815 2417 AGGAGAGG A UGCACAGU 1441 ACTGTGCA GGCTAGCTACAACGACCTCTCCT 3816 2444 CUUUAGAG A CAGGGACU 1442 AGTCCCTG GGCTAGCTACAACGACTCTAAAG 3817 2450 AGACAGGG A CUGUAUAA 1443 TTATACAG GGCTAGCTACAACGACCCTGTCT 3818 2459 CUGUAUAA A CAAGCCUA 1444 TAGGCTTG GGCTAGCTACAACGATTATACAG 3819 2468 CAAGCCUA A CAUUGGUG 1445 CACCAATG GGCTAGCTACAACGATAGGCTTG 3820 2482 GUGCAAAG A UUGCCUCU 1446 AGAGGCAA GGCTAGCTACAACGACTTTGCAC 3821 2494 CCUCUUGA A UUAAAAAA 1447 TTTTTTAA GGCTAGCTACAACGATCAAGAGG 3822 2507 AAAAAAAA A CUAGAAAA 1448 TTTTCTAG GGCTAGCTACAACGATTTTTTTT 3823

[0309] TABLE VIII Human BACE Amberzyme Ribozyme and Target Sequences PosSubstrate Seq ID Amberzyme Seq ID 11 ACGCGUCC G CAGCCCGC 960 GCGGGCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGACGCGU 3824 18 CGCAGCCC G CCCGGGAG961 CUCCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCUGCG 3825 29CGGGAGCU G CGAGCCGC 962 GCGGCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGCUCCCG 3826 31 GGAGCUGC G AGCCGCGA 963 UCGCGGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCAGCUCC 3827 36 UGCGAGCC G CGAGCUGG 964 CCAGCUCGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCUCGCA 3828 38 CGAGCCGC G AGCUGGAU965 AUCCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGCUCG 3829 58GGUGGCCU G AGCAGCCA 966 UGGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGCCACC 3830 69 CAGCCAAC G CAGCCGCA 967 UCCGGCUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUUGGCUG 3831 75 ACGCAGCC G CAGGAGCC 968 GGCUCCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCUGCGU 3832 94 GAGCCCUU G CCCCUGCC969 GUCAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGGCUC 3833 100UUGCCCCU G CCCGCGCC 970 GGCGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGGGCAA 3834 104 CCCUGCCC G CGCCGCCG 971 CGGCGGCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGCAGGG 3835 106 CUGCCCGC G CCGCCGCC 972 GGCGGCGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGGCAG 3836 109 CCCGCGCC G CCGCCCGC973 GCGGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCGCGGG 3837 112GCGCCGCC G CCCGCCGG 974 CCGGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGCGGCGC 3838 116 CGCCGCCC G CCGGGGGG 975 CCCCCCGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGCGGCG 3839 137 GGGAAGCC G CCACCGGC 976 GCCGGUGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCUUCCC 3840 148 ACCGGCCC G CCAUGCCC977 GGGCAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCGGU 3841 153CCCGCCAU G CCCGCCCC 978 GGGGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAUGGCGGG 3842 157 CCAUGCCC G CCCCUCCC 979 GGGAGGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGCAUGG 3843 172 CCAGCCCC G CCGGGAGC 980 GCUCCCGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGCUGG 3844 183 GGGAGCCC G CGCCCGCU981 AGCGGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCUCCC 3845 185GAGCCCGC G CCCGCUGC 982 GCAGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGCGGGCUC 3846 189 CCGCGCCC G CUGCCCAG 983 CUGGGCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGCGCGG 3847 192 CGCCCGCU G CCCAGGCU 984 AGCCUGGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGGGCG 3848 205 GGCUGGCC G CCGCCGUG985 CACGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCAGCC 3849 208UGGCCGCC G CCGUGCCG 986 CGGCACGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGCGGCCA 3850 213 GCCGCCGU G CCGAUGUA 987 UACAUCGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACGGCGGC 3851 216 GCCGUGCC G AUGUAGCG 988 CGCUACAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCACGGC 3852 250 UCUCCCCU G CUCCCGUG989 CACGGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGAGA 3853 258GCUCCCGU G CUCUGCGG 990 CCGCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGACGGGAGC 3854 263 CGUGCUCU G CGGAUCUC 991 GAGAUCCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGAGCACG 3855 276 UCUCCCCU G ACCGCUCU 992 AGAGCGGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGAGA 3856 280 CCCUGACC G CUCUCCAC993 GUGGAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCAGGG 3857 320AGGGCCCU G CAGGCCCU 994 AGGGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGGCCCU 3858 337 GGCGUCCU G AUGCCCCC 995 GGGGGCAU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGACGCC 3859 340 GUCCUGAU G CCCCCAAG 996 CUUGGGGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGGAC 3860 360 CCUCUCCU G AGAAGCCA997 UGGCUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGAGG 3861 397GGGCAGGC G CCAGGGAC 998 GUCCCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGCCUGCCC 3862 420 GGGCCAGU G CGAGCCCA 999 UGGGCUCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACUGGCCC 3863 422 GCCAGUGC G AGCCCAGA 1000 UCUGGGCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCACUGGC 3864 437 GAGGGCCC G AAGGCCGG1001 CCGGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCCUC 3865 468CAAGCCCU G CCCUGGCU 1002 AGCCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGGCUUG 3866 480 UGGCUCCU G CUGUGGAU 1003 AUCCACAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGAGCCA 3867 493 GGAUGGGC G CGGGAGUG 1004 CACUCCCGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCAUCC 3868 501 GCGGGAGU G CUGCCUGC1005 GCAGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCCCGC 3869 504GGAGUGCU G CCUGCCCA 1006 UGGGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGCACUCC 3870 508 UGCUGCCU G CCCACGGC 1007 GCCGUGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGCAGCA 3871 537 AUCCGGCU G CCCCUGCG 1008 CGCAGGGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCGGAU 3872 543 CUGCCCCU G CGCAGCGG1009 CCGCUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCAG 3873 545GCCCCUGC G CAGCGGCC 1010 GGCCGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGCAGGGGC 3874 562 UGGGGGGC G CCCCCCUG 1011 CAGGGGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCCCCCCA 3875 576 CUGGGGCU G CGGCUGCC 1012 GGCAGCCGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCCAG 3876 582 CUGCGGCU G CCCCGGGA1013 UCCCGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCGCAG 3877 595GGGAGACC G ACGAAGAG 1014 CUCUUCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGUCUCCC 3878 598 AGACCGAC G AAGAGCCC 1015 GGGCUCUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUCGGUCU 3879 607 AAGAGCCC G AGGAGCCC 1016 GGGCUCCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCUCUU 3880 654 GACAACCU G AGGGGCAA1017 UUGCCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUUGUC 3881 690GUGGAGAU G ACCGUGGG 1018 CCCACGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAUCUCCAC 3882 708 AGCCCCCC G CAGACGCU 1019 AGCGUCUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGGGGCU 3883 714 CCGCAGAC G CUCAACAU 1020 AUGUUGAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCUGCGG 3884 751 GUAACUUU G CAGUGGGU1021 ACCCACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACUUAC 3885 760CAGUGGGU G CUGCCCCC 1022 GGGGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGACCCACUG 3886 763 UGGGUGCU G CCCCCCAC 1023 GUGGGGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCACCCA 3887 780 CCCUUCCU G CAUCGCUA 1024 UAGCGAUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAAGGG 3888 785 CCUGCAUC G CUACUACC1025 GGUAGUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUGCAGG 3889 843GUGUAUGU G CCCUACAC 1026 GUGUAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGACAUACAC 3890 883 UGGGCACC G ACCUGGUA 1027 UACCAGGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGUGCCCA 3891 921 GUCACUGU G CGUGCCAA 1028 UUGGCACGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUGAC 3892 925 CUGUGCGU G CCAACAUU1029 AAUGUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCACAG 3893 934CCAACAUU G CUGCCAUC 1030 GAUGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAAUGUUGG 3894 937 ACAUUGCU G CCAUCACU 1031 AGUGAUGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCAAUGU 3895 946 CCAUCACU G AAUCAGAC 1032 GUCUGAUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGAUGG 3896 1006 UGGCCUAU GCUGAGAUU 1033 AAUCUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAGGCCA 38971009 CCUAUGCU G AGAUUGCC 1034 GGCAAUCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCAUAGG 3898 1015 CUGAGAUU G CCAGGCCU 1035 AGGCCUGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCUCAG 3899 1024 CCAGGCCU GACGACUCC 1036 GGAGUCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCCUGG 39901027 GGCCUGAC G ACUCCCUG 1037 CAGGGAGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUCAGGCC 3901 1048 CUUUCUUU G ACUCUCUG 1038 CAGAGAGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGAAAG 3902 1092 UUCUCCCU GCAGCUUUG 1039 CAAAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGAGAA 39031105 UUUGUGGU G CUGGCUUC 1040 GAAGCCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACCACAAA 3904 1129 ACCAGUCU G AAGUGCUG 1041 CAGCACUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACUGGU 3905 1134 UCUGAAGU GCUGGCCUC 1042 GAGGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUCAGA 39061158 GGGAGCAU G AUCAUUGG 1043 CCAAUGAU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUGCUCCC 3907 1174 GAGGUAUC G ACCACUCG 1044 CGAGUGGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUACCUC 3908 1182 GACCACUC GCUGUACAC 1045 GUGUACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUGGUC 39091234 GGUAUUAU G AGGUGAUC 1046 GAUCACCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUAAUACC 3910 1239 UAUGAGGU G AUCAUUGU 1047 ACAAUGAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCAUA 3911 1248 AUCAUUGU GCGGGUGGA 1048 UCCACCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAUGAU 39121275 CAGGAUCU G AAAAUGGA 1049 UCCAUUUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGAUCCUG 3913 1286 AAUGGACU G CAAGGAGU 1050 ACUCCUUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCCAUU 3914 1303 ACAACUAU GACAAGAGC 1051 GCUCUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAGUUGU 39151344 CUUCGUUU G CCCAAGAA 1052 UUCUUGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAACGAAG 3916 1360 AAGUGUUU G AAGCUGCA 1053 UGCAGCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACACUU 3917 1366 UUGAAGCU GCAGUCAAA 1054 UUUGACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUCAA 39181411 AGUUCCCU G AUGGUUUC 1055 GAAACCAU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGGAACU 3919 1442 GCUGGUGU G CUGGCAAG 1056 CUUGCCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACCAGC 3920 1504 UAAUGGGU GAGGUUACC 1057 GGUAACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCAUUA 39211526 GUCCUUCC G CAUCACCA 1058 UGGUGAUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGAAGGAC 3922 1542 AUCCUUCC G CAGCAAUA 1059 UAUUGCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAAGGAU 3923 1554 CAAUACCU GCGGCCAGU 1060 ACUGGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUAUUG 39241588 CCCAAGAC G ACUGUUAC 1061 GUAACAGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUCUUGGG 3925 1603 ACAAGUUU G CCAUCUCA 1062 UGAGAUGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACUUGU 3926 1672 UUGUCUUU GAUCGGGCC 1063 GGCCCGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGACAA 39271682 UCGGGCCC G AAAACGAA 1064 UUCGUUUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGCCCGA 3928 1688 CCGAAAAC G AAUUGGCU 1065 AGCCAAUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUUUCGG 3929 1699 UUGGCUUU GCUGUCAGC 1066 GCUGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGCCAA 39301708 CUGUCAGC G CUUGCCAU 1067 AUGGCAAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCUGACAG 3931 1712 CAGCGCUU G CCAUGUGC 1068 GCACAUGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGCGCUG 3932 1719 UGCCAUGU GCACCAUGA 1069 UCAUCGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUGGCA 39331723 AUGUGCAC G AUGAGUUC 1070 GAACUCAU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUGCACAU 3934 1726 UGCACGAU G AGUUCAGG 1071 CCUGAACUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCGUGCA 3935 1807 AGACAGAU GAGUCAACC 1072 GGUUGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUGUCU 39361821 ACCCUCAU G ACCAUAGC 1073 GCUAUGGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUGAGGGU 3937 1843 UCAUGGCU G CCAUCUGC 1074 GCAGAUGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAUGA 3938 1850 UGCCAUCU GCGCCCUCU 1075 AGAGGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUGGCA 39391852 CCAUCUGC G CCCUCUUC 1076 GAAGAGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCAGAUGG 3940 1863 CUCUUCAU G CUGCCACU 1077 AGUGGCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAAGAG 3941 1866 UUCAUGCU GCCACUCUG 1078 CAGAGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAUGAA 39421874 GCCACUCU G CCUCAUGG 1079 CCAUGAGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGAGUGGC 3943 1895 UCAGUGGC G CUGCCUCC 1080 GGAGGCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCACUGA 3944 1898 CUGGCGCU GCCUCCGCU 1081 AGCGGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCCAC 39451904 CUGCCUCC G CUGCCUGC 1082 GCAGGCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGAGGCAG 3946 1907 CCUCCGCU G CCUGCGCC 1083 GGCCCAGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGGAGG 3947 1911 CGCUGCCU GCGCCAGCA 1084 UGCUGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCAGCG 39481913 CUGCCUGC G CCAGCAGC 1085 GCUGCUGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCAGGCAG 3949 1924 AGCAGCAU G AUGACUUU 1086 AAACUCAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCUGCU 3950 1927 AGCAUGAU GACUUUGCU 1087 AGCAAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAUGCU 39511933 AUGACUUU G CUGAUGAC 1088 GUCAUCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAAGUCAU 3952 1936 ACUUUGCU G AUGACAUC 1089 GAUGUCAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAAAGU 3953 1939 UUGCUGAU GACAUCUCC 1090 GGAGAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGCAA 39541950 AUCUCCCU G CUCAAGUG 1091 CACUUCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGGAGAU 3955 1953 UCCCUGCU G AAGUGAGG 1092 CCUCACUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGGGA 3956 1958 GCUGAAGU GAGGAGGCC 1093 GGCCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUCAGC 39572087 CACCAAAU G CCUCUGCC 1094 GGCAGAGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUUUGGUG 3958 2093 AUGCCUCU G CCUUGAUG 1095 CAUCAAGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGCAU 3959 2098 UCUGCCUU GAUGGAGAA 1096 UUCUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGCAGA 39602179 AGCACUCU G CUGGCGGG 1097 CCCGCCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGAGUGCU 3961 2227 GAAAUUCU G CUGCUUGA 1098 UCAAGCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAUUUC 3962 2230 AUUCUGCU CCUUGAAAC 1099 GUUUCAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGAAU 39632234 UGCUGCUU G AAACUUCA 1100 UGAAGUUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAGCAGCA 3964 2248 UCAGCCCU G AACCUUUG 1101 CAAAGGUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCUGA 3965 2329 CAUCACAC GCAGGUUAC 1102 GUAACCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGUGAUG 39662393 GUUUCCCU G CUGGCCAA 1103 UUGGCCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGGAAAC 3967 2419 GAGAGGAU G CACAGUUU 1104 AAACUGUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCUCUC 3968 2428 CACAGUUU GCUAUUUGC 1105 GCAAAUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACUGUG 39692435 UGCUAUUU G CUUUAGAG 1106 CUCUAAAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAAUAGCA 3970 2476 ACAUUGGU G CAAAGAUU 1107 AAUCUUUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAAUGU 3971 2485 CAAAGAUU GCCUCUUGA 1108 UCAAGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCUUUG 39722492 UGCCUCUU G AAUUAAAA 1109 UUUUAAUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAGAGGCA 3973 219 GUGCCGAU G UAGCGGGC 1110 GCCCGCUAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCGGCAC 3974 483 CUCCUGCU G UGGAUGGG1111 CCCAUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGGAG 3975 634GCAGCUUU G UGGAGAUG 1112 CAUCUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAAAGCUGC 3976 804 AGGCAGCU G UCCAGCAC 1113 GUGCUGGA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCUGCCU 3977 835 GGAAGGGU G UGUAUGUG 1114 CACAUACAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCUUCC 3978 837 AACGGUGU G UAUGUGCC1115 GGCACAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACCCUU 3979 841GUGUGUAU G UGCCCUAC 1116 GUAGCGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAUACACAC 3980 919 ACGUCACU G UGCGUGCC 1117 GGCACGCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGUGACGU 3981 1100 GCAGCUUU G UGGUGCUG 1118 CAGCACCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGCUGC 3982 1144 UGGCCUCU GUCGGAGGG 1119 CCCUCCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGCCA 39831185 CACUCGCU G UACACAGG 1120 CCUGUGUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCGAGUG 3984 1246 UGAUCAUU G UGCGGGUG 1121 CACCCGCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGAUCA 3985 1315 AGAGCAUU GUGGACACU 1122 ACUGUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGCUCU 39861356 AAGAAAGU G UUUGAAGC 1123 GCUUCAAA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACUUUCUU 3987 1440 CAGCUGGU G UGCUGGCA 1124 UGCCAGCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAGCUG 3988 1570 UGGAAGAU GUGGCCACG 1125 CGUGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUUCCA 39891592 AGACGACU G UUACAAGU 1126 ACUUGUAA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGUCGUCU 3990 1630 CGGGCACU G UUAUGGGA 1127 UCCCAUAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGCCCG 3991 1642 UGGGAGCU GUUAUCAUG 1128 CAUGAUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCCA 39921666 UCUACGUU G UCUUUGAU 1129 AUCAAAGA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AACGUAGA 3993 1702 GCUUUGCU G UCAGCGCU 1130 AGCGCUGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAAAGC 3994 1717 CUUGCCAU GUGCACGAU 1131 AUCGUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGCAAG 39951759 GCCCUUUU G UCACCUUG 1132 CAAGGUGA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAAAGGGC 3996 1781 GGAAGACU G UGGCUACA 1133 UGUAGCCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCUUCC 3997 1834 UAGCCUAU GUCAUGGCU 1134 AGCCAUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAGGCUA 39981884 CUCAUGGU G UGUCAGUG 1135 CACUGACA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACCAUGAG 3999 1886 CAUGGUGU G UCAGUGGC 1136 GCCACUGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACCAUG 4000 2048 UGGCACCU GUGGCCAGA 1137 UCUGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGCCA 40012139 CAGGGACU G UACCUGUA 1138 UACAGGUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGUCCCUG 4002 2145 CUGUACCU G UAGGAAAC 1139 GUUUCCUAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUACAG 4003 2256 GAACCUUU GUCCACCAU 1140 AUGGUGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGGUUC 40042346 CUUGGCGU G UGUCCCUG 1141 CAGGGACA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACGCCAAG 4005 2348 UGGCGUGU G UCCCUGUG 1142 CACAGGGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACGCCA 4006 2354 GUGUCCCU GUGGUACCC 1143 GGGUACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGACAC 40072385 CCAAGCUU G UUUCCCUG 1144 CAGGGAAA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAGCUUGG 4008 2453 CAGGGACU G UAUAAACA 1145 UGUUUAUAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCCCUG 4009 14 CGUCCGCA G CCCGCCCG1146 CGGGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGGACG 4010 26GCCCGGGA G CUGCGAGC 1147 GCUCGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCCCGGGC 4011 33 AGCUGCGA G CCGCGAGC 1148 GCUCGCGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCGCAGCU 4012 40 AGCCGCGA G CUGGAUUA 1149 UAAUCCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCGGCU 4013 51 GGAUUAUG G UGGCCUGA1150 UCAGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUAAUCC 4014 54UUAUGGUG G CCUGAGCA 1151 UGCUCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCACCAUAA 4015 60 UGGCCUGA G CAGCCAAC 1152 GUUGGCUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCAGGCCA 4016 63 CCUGAGCA G CCAACGCA 1153 UGCGUUGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCAGG 4017 72 CCAACGCA G CCGCAGGA1154 UCCUGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGUUGG 4018 81CCGCAGGA G CCCGGAGC 1155 GCUCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCCUGCGG 4019 88 AGCCCGGA G CCCUUGCC 1156 GGCAAGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCCGGGCU 4020 134 CCAGGGAA G CCGCCACC 1157 GGUGGCGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCUGG 4021 144 CGCCACCG G CCCGCCAU1158 AUGGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUGGCG 4022 167CCCUCCCA G CCCCGCCG 1159 CGGCGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGGGAGGG 4023 179 CGCCGGGA G CCCGCGCC 1160 GGCGCGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCCCGGCG 4024 198 CUGCCCAG G CUGGCCGC 1161 GCGGCCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCAG 4025 202 CCAGGCUG G CCGCCGCC1162 GGCGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGG 4026 211CCGCCGCC G UGCCGAUG 1163 CAUCGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGCGGCGG 4027 222 CCGAUGUA G CGGGCUCC 1164 GGAGCCCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UACAUCGG 4028 226 UGUAGCGG G CUCCGGAU 1165 AUCCGGAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCUACA 4029 239 GGAUCCCA G CCUCUCCC1166 GGGAGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGAUCC 4030 256CUGCUCCC G UGCUCUGC 1167 GCAGAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGGAGCAG 4031 290 UCUCCACA G CCCGGACC 1168 GGUCCGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGUGGAGA 4032 304 ACCCGGGG G CUGGCCCA 1169 UGGGCCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCGGGU 4033 308 GGGGGCUG G CCCAGGGC1170 GCCCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCCCC 4034 315GGCCCAGG G CCCUGCAG 1171 CUGCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCUGGGCC 4035 324 CCCUGCAG G CCCUGGCG 1172 CGCCAGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUGCAGGG 4036 330 AGGCCCUG G CGUCCUGA 1173 UCAGGACGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGCCU 4037 332 GCCCUGGC G UCCUGAUG1174 CAUCAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCAGGGC 4038 348GCCCCCAA G CUCCCUCU 1175 AGAGGGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUUGGGGGC 4039 365 CCUGAGAA G CCACCAGC 1176 GCUGGUGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCUCAGG 4040 372 AGCCACCA G CACCACCC 1177 GGGUGGUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUGGCU 4041 391 ACUUGGGG G CAGGCGCC1178 GGCGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCAAGU 4042 395GGGGGCAG G CGCCAGGG 1179 CCCUGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCUGCCCCC 4043 410 GGACGGAC G UGGGCCAG 1180 CUGGCCCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUCCGUCC 4044 414 GGACGUGG G CCAGUGCG 1181 CGCACUGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACGUCC 4045 418 GUGGGCCA G UGCGAGCC1182 GGCUCGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCCAC 4046 424CAGUGCGA G CCCAGAGG 1183 CCUCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCGCACUG 4047 433 CCCAGAGG G CCCGAAGG 1184 CCUUCGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCUCUGGG 4048 441 GCCCGAAG G CCGGGGCC 1185 GGCCCCGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCGGGC 4049 447 AGGCCGGG G CCCACCAU1186 AUGGUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGGCCU 4050 457CCACCAUG G CCCAAGCC 1187 GGCUUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCAUGGUGG 4051 463 UGGCCCAA G CCCUGCCC 1188 GGGCAGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUGGGCCA 4052 474 CUGCCCUG G CUCCUGCU 1189 AGCAGGAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGCAG 4053 491 GUGGAUGG G CGCGGGAG1190 CUCCCGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUCCAC 4054 499GCGCGGGA G UGCUGCCU 1191 AGGCAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCCCGCGC 4055 515 UGCCCACG G CACCCAGC 1192 GCUGGGUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGUGGGCA 4056 522 GGCACCCA G CACGGCAU 1193 AUGCCGUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUGCC 4057 527 CCAGCACG G CAUCCGGC1194 GCCGGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUGCUGG 4058 534GGCAUCCG G CUGCCCCU 1195 AGGGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCGGAUGCC 4059 548 CCUGCGCA G CGGCCUGG 1196 CCAGGCCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGCGCAGG 4060 551 GCGCAGCG G CCUGGGGG 1197 CCCCCAGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUGCGC 4061 560 CCUGGGGG G CGCCCCCC1198 GGGGGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCCAGG 4062 573CCCCUGGG G CUGCGGCU 1199 AGCCGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCCAGGGG 4063 579 GGGCUGCG G CUGCCCCG 1200 CGGGGCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGCAGCCC 4064 603 GACGAAGA G CCCGAGGA 1201 UCCUCGGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCGUC 4065 612 CCCGAGGA G CCCGGCCG1202 CGGCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCGGG 4066 617GGAGGCCG G CCGGAGGG 1203 CCCUCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCGGGCUCC 4067 626 CCGGAGGG G CAGCUUUG 1204 CAAAGCUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCCUCCGG 4068 629 GAGGGGCA G CUUUGUGG 1205 CCACAAAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCCUC 4069 643 UGGAGAUG G UGGACAAC1206 GUUGUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUCCA 4070 659CCUGAGGG G CAAGUCGG 1207 CCGACUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCCUCAGG 4071 663 AGGGGCAA G UCGGGGCA 1208 UGCCCCGA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUGCCCCU 4072 669 AAGUCGGG G CAGGGCUA 1209 UAGCCCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGACUU 4073 674 GGGGCAGG G CUACUACG1210 CGUAGUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGCCCC 4074 682GCUACUAC G UGGAGAUG 1211 CAUCUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGUAGUAGC 4075 694 AGAUGACC G UGGGCAGC 1212 GCUGCCCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGUCAUCU 4076 698 GACCGUGG G CAGCCCCC 1213 GGGGGCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACGGUC 4077 701 CGUGGGCA G CCCCCCGC1214 GCGGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCACG 4078 727ACAUCCUG G UGGAUACA 1215 UGUAUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCAGGAUGU 4079 737 GGAUACAG G CAGCAGUA 1216 UACUGCUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUGUAUCC 4080 740 UACAGGCA G CAGUAACU 1217 AGUUACUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUGUA 4081 743 AGGCAGCA G UAACUUUG1218 CAAAGUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGCCU 4082 754ACUUUGCA G UGGGUGCU 1219 AGCACCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGCAAAGU 4083 758 UGCAGUGG G UGCUGCCC 1220 GGGCAGCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCACUGCA 4084 798 UACCAGAG G CAGCUGUC 1221 GACAGCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGGUA 4085 801 CAGAGGCA G CUGUCCAG1222 CUGGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUCUG 4086 809GCUGUCCA G CACAUACC 1223 GGUAUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGGACAGC 4087 833 CCGGAAGG G UGUGUAUG 1224 CAUACACA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCUUCCGG 4088 857 CACCCAGG G CAAGUGGG 1225 CCCACUUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGGGUG 4089 861 CAGGGCAA G UGGGAAGG1226 CCUUCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCCCUG 4090 873GAAGGGGA G CUGGGCAC 1227 CUGCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCCCCUUC 4091 878 GGAGCUGG G CACCGACC 1228 GGUCGGUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCAGCUCC 4092 889 CCGACCUG G UAAGCAUC 1229 GAUGCUUAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUCGG 4093 893 CCUGGUAA G CAUCCCCC1230 GGGGGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUACCAGG 4094 905CCCCCAUG G CCCCAACG 1231 CGUUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCAUGGGGG 4095 913 GCCCCAAC G UCACUGUG 1232 CACAGUGA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUUGGGGC 4096 923 CACUGUGC G UGCCAACA 1233 UGUUGGCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCACAGUG 4097 957 UCAGACAA G UUCUUCAU1234 AUGAAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUCUGA 4098 971CAUCAACG G CUCCAACU 1235 AGUUGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCGUUGAUG 4099 986 CUGGGAAG G CAUCCUGG 1236 CCAGGAUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUUCCCAG 4100 996 AUCCUGGG G CUGGCCUA 1237 UAGGCCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGGAU 4101 1000 UGGGGCUG GCCUAUGCU 1238 AGCAUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCCCA 41021020 AUUGCCAG G CCUGACGA 1239 UCGUCAGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUGGCAAU 4103 1038 UCCCUGGA G CCUUUCUU 1240 AAGAAAGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGGGA 4104 1057 ACUCUCUG GUAAAGCAG 1241 CUGCUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGAGU 41051062 CUGGUAAA G CAGACCCA 1242 UGGGUCUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUUACCAG 4106 1072 AGACCCAC G UUCCCAAC 1243 GUUGGGAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGGUCU 4107 1095 UCCCUGCA GCUUUGUGG 1244 CCACAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGGGA 41081103 GCUUUGUG G UGCUGGCU 1245 AGCCAGCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACAAAGC 4109 1109 UGGUGCUG G CUUCCCCC 1246 GGGGGAAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCACCA 4110 1125 CUCAACCA GUCUGAAGU 1247 ACUUCAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUGAG 41111132 AGUCUGAA G UGCUGGCC 1248 GGCCAGCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCAGACU 4112 1138 AAGUGCUG G CCUCUGUC 1249 GACAGAGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCACUU 4113 1154 CGGAGGGA GCAUGAUCA 1250 UGAUCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUCCG 41141169 CAUUGGAG G UAUCGACC 1251 GGUCGAUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUCCAAUG 4115 1193 GUACACAG G CAGUCUCU 1252 AGAGACUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUGUAC 4116 1196 CACAGGCA GUCUCUGGU 1253 ACCAGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUGUG 41171203 AGUCUCUG G UAUACACC 1254 GGUGUAUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGAGACU 4118 1218 CCCAUCCG G CGGGAGUG 1255 CACUCCCGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGAUGGG 4119 1224 CGGCGGGA GUGGUAUUA 1256 UAAUACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCGCCG 41201227 CGGGAGUG G UAUUAUGA 1257 UCAUAAUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACUCCCG 4121 1237 AUUAUGAG G UGAUCAUU 1258 AAUGAUCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAUAAU 4122 1252 UUGUGCGG GUGGAGAUC 1259 GAUCUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCACAA 41231293 UGCAAGGA G UACAACUA 1260 UAGUUGUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCCUUGCA 4124 1310 UGACAAGA G CAUUGUGG 1261 CCACAAUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUGUCA 4125 1322 UGUGGACA GUGGCACCA 1262 UGGUGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCCACA 41261325 GGACAGUG G CACCACCA 1263 UGGUGGUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACUGUCC 4127 1340 CAACCUUC G UUUGCCCA 1264 UGGGCAAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGGUUG 4128 1354 CCAAGAAA GUGUUUGAA 1265 UUCAAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCUUGG 41291363 UGUUUGAA G CUGCAGUC 1266 GACUGCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCAAACA 4130 1369 AAGCUGCA G UCAAAUCC 1267 GGAUUUGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCUU 4131 1384 CCAUCAAG GCAGCCUCC 1268 GGAGGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGAUGG 41321387 UCAAGGCA G CCUCCUCC 1269 GGAGGAGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGCCUUGA 4133 1404 ACGGAGAA G UUCCCUGA 1270 UCAGGGAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCCGU 4134 1415 CCCUGAUG GUUUCUGGC 1271 GCCAGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAGGG 41351422 GGUUUCUG G CUAGGAGA 1272 UCUCCUAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGAAACC 4136 1431 CUAGGAGA G CAGCUGGU 1273 ACCAGCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCCUAG 4137 1434 GGAGAGCA GCUGGUGUG 1274 CACACCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCUCC 41381438 AGCAGCUG G UGUGCUGG 1275 CCAGCACA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGCUGCU 4139 1446 GUGUGCUG G CAAGCAGG 1276 CCUGCUUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCACAC 4140 1450 GCUGGCAA GCAGGCACC 1277 GGUGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCCAGC 41411454 GCAAGCAG G CACCACCC 1278 GGGUGGUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUGCUUGC 4142 1480 UUUUCCCA G UCAUCUCA 1279 UGAGAUGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGAAAA 4143 1502 CCUAAUGG GUGAGGUUA 1280 UAACCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUUAGG 41441507 UGGGUGAG G UUACCAAC 1281 GUUGGUAA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUCACCCA 4145 1518 ACCAACCA G UCCUUCCG 1282 CGGAAGGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUGGU 4146 1545 CUUCCGCA GCAAUACCU 1283 AGGUAUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGGAAG 41471557 UACCUGCG G CCAGUGGA 1284 UCCACUGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGCAGGUA 4148 1561 UGCGGCCA G UGGAAGAU 1285 AUCUUCCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCGCA 4149 1573 AAGAUGUG GCCACGUCC 1286 GGACGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAUCUU 41501578 GUGGCCAC G UCCCAAGA 1287 UCUUGGGA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUGGCCAC 4151 1599 UGUUACAA G UUUGCCAU 1288 AUGGCAAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUAACA 4152 1614 AUCUCACA GUCAUCCAC 1289 GUGGAUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGAGAU 41531625 AUCCACGG G CACUGUUA 1290 UAACAGUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCGUGGAU 4154 1639 UUAUGGGA G CUGUUAUC 1291 GAUAACAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCAUAA 4155 1655 CAUGGAGG GCUUCUACG 1292 CGUAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCCAUG 41561663 GCUUCUAC G UUGUCUUU 1293 AAAGACAA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUAGAAGC 4157 1678 UUGAUCGG G CCCGAAAA 1294 UUUUCGGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAUCAA 4158 1694 ACGAAUUG GCUUUGCUG 1295 CAGCAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUUCGU 41591706 UGCUGUCA G CGCUUGCC 1296 GGCAAGCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGACAGCA 4160 1728 CACGAUGA G UUCAGGAC 1297 GUCCUGAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUCGUG 4161 1738 UCAGGACG GCAGCGGUG 1298 CACCGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUCCUGA 41621741 GGACGGCA G CGGUGGAA 1299 UUCCACCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGCCGUCC 4163 1744 CGGCAGCG G UGGAAGGC 1300 GCCUUCCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUGCCG 4164 1751 GGUGGAAG GCCCUUUUG 1301 CAAAAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCCACC 41651784 AGACUGUG G CUACAACA 1302 UGUUGUAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACAGUCU 4166 1809 ACAGAUGA G UCAACCCU 1303 AGGGUUGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUCUGU 4167 1828 UGACCAUA GCCUAUGUC 1304 GACAUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGGUCA 41681840 AUGUCAUG G CUGCCAUC 1305 GAUGGCAG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAUGACAU 4169 1882 GCCUCAUG G UGUGUCAG 1306 CUGACACAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGAGGC 4170 1890 GUGUGUCA GUGGCGCUG 1307 CAGCGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACACAC 41711893 UGUCAGUG G CGCUGCCU 1308 AGGCAGCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACUGACA 4172 1917 CUGCGCCA G CAGCAUGA 1309 UCAUCCUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCGCAG 4173 1920 CGCCAGCA GCAUGAUGA 1310 UCAUCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGGCG 41741956 CUGCUGAA G UGAGGAGG 1311 CCUCCUCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCAGCAG 4175 1964 GUGAGGAG G CCCAUGGG 1312 CCCAUGGGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCAC 4176 1972 GCCCAUGG GCAGAAGAU 1313 AUCUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUGGGC 41772006 ACACCUCC G UGGUUCAC 1314 GUGAACCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGAGGUGU 4178 2009 CCUCCGUG G UUCACUUU 1315 AAAGUGAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACGGAGG 4179 2019 UCACUUUG GUCACAAGU 1316 ACUUGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAGUGA 41802026 GGUCACAA G UAGGAGAC 1317 GUCUCCUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUGUGACC 4181 2042 CACAGAUG G CACCUGUG 1318 CACAGGUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUGUG 4182 2051 CACCUGUG GCCAGAGCA 1319 UGCUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGGUG 41832057 UGGCCAGA G CACCUCAG 1320 CUGAGGUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCUGGCCA 4184 2114 AGGAAAAG G CUGGCAAG 1321 CUUGCCAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUUCCU 4185 2118 AAAGGCUG GCAAGGUGG 1322 CCACCUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUUU 41862123 CUGGCAAG G UGGGUUCC 1323 GGAACCCA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUUGCCAG 4187 2127 CAAGGUGG G UUCCAGGG 1324 CCCUGGAAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACCUUG 4188 2172 AGAAAGAA GCACUCUGC 1325 GCAGAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUUCU 41892183 CUCUGCUG G CGGGAAUA 1326 UAUUCCCG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGCAGAG 4190 2198 UACUCUUG G UCACCUCA 1327 UCAGGUGAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGAGUA 4191 2214 AAAUUUAA GUCGGGAAA 1328 UUUCCCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAAAUUU 41922243 AAACUUCA G CCCUGAAC 1329 GUUCAGGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGAAGUUU 4193 2288 AACCCAAA G UAUUCUUC 1330 GAAGAAUAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGGGUU 4194 2305 UUUUCUUA GUUUCAGAA 1331 UUCUGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAGAAAA 41952314 UUUCAGAA G UACUGGCA 1332 UGCCAGUA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCUGAAA 4196 2320 AAGUACUG G CAUCACAC 1333 GUGUGAUGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUACUU 4197 2333 ACACGCAG GUUACCUUG 1334 CAAGGUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCGUGU 41982342 UUACCUUG G CGUGUGUC 1335 GACACACG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAAGGUAA 4199 2344 ACCUUGGC G UGUGUCCC 1336 GGGACACAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCAAGGU 4200 2357 UCCCUGUG GUACCCUGG 1337 CCAGGGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGGGA 42012365 GUACCCUG G CAGAGAAG 1338 CUUCUCUG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGGGUAC 4202 2381 GAGACCAA G CUUGUUUC 1339 GAAACAAGGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGUCUC 4203 2397 CCCUGCUG GCCAAAGUC 1340 GACUUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCAGGG 42042403 UGGCCAAA G UCAGUAGG 1341 CCUACUGA GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUUGGCCA 4205 2407 CAAAGUCA G UAGGAGAG 1342 CUCUCCUAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACUUUG 4206 2424 GAUGCACA GUUUGCUAU 1343 AUAGCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGCAUC 42072463 AUAAACAA G CCUAACAU 1344 AUGUUAGG GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUGUUUAU 4208 2474 UAACAUUG G UGCAAAGA 1345 UCUUUGCAGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUGUUA 4209 22 GCCCGCCC G GGAGCUGC1449 GCAGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCGGGC 4210 23CCCGCCCG G GAGCUGCG 1450 CGCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCGGGCGGG 4211 24 CCGCCCGG G AGCUGCGA 1451 UCGCAGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCGGGCGG 4212 43 CGCGAGCU G GAUUAUGG 1452 CCAUAAUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCGCG 4213 44 GCGAGCUG G AUUAUGGU1453 ACCAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUCGC 4214 50UGGAUUAU G GUGGCCUG 1454 CAGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAUAAUCCA 4215 53 AUUAUGGU G GCCUGAGC 1455 GCUCAGGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACCAUAAU 4216 78 CAGCCGCA G GAGCCCGG 1456 CCGGGCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGGCUG 4217 79 AGCCGCAG G AGCCCGGA1457 UCCGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCGGCU 4218 85AGGAGCCC G GAGCCCUU 1458 AAGGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGGCUCCU 4219 86 GGAGCCCG G AGCCCUUG 1459 CAAGGGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGGGCUCC 4220 119 CGCCCGCC G GGGGGACC 1460 GGUCCCCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCGGGCG 4221 120 GCCCGCCG G GGGGACCA1461 UGGUCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCGGGC 4222 121CCCGCCGG G GGGACCAG 1462 CUGGUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCGGCGGG 4223 122 CCGCCGGG G GGACCAGG 1463 CCUGGUCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCCGGCGG 4224 123 CGCCGGGG G GACCAGGG 1464 CCCUGGUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCGGCG 4225 124 GCCGGGGG G ACCAGGGA1465 UCCCUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCCGGC 4226 129GGGGACCA G GGAAGCCG 1466 CGGCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGGUCCCC 4227 130 GGGACCAG G GAAGCCGC 1467 GCGGCUUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUGGUCCC 4228 131 GGACCAGG G AAGCCGCC 1468 GGCGGCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGGUCC 4229 143 CCGCCACC G GCCCGCCA1469 UGGCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGGCGG 4230 175GCCCCGCC G GGAGCCCG 1470 CGGGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGCGGGGC 4231 176 CCCCGCCG G GAGCCCGC 1471 GCGGGCUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGGCGGGG 4232 177 CCCGCCGG G AGCCCGCG 1472 CGCGGGCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGCGGG 4233 197 GCUGCCCA G GCUGGCCG1473 CGGCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCAGC 4234 201CCCAGGCU G GCCGCCGC 1474 GCGGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGCCUGGG 4235 224 GAUGUAGC G GGCUCCGG 1475 CCGGAGCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCUACAUC 4236 225 AUGUAGCG G GCUCCGGA 1476 UCCGGAGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUACAU 4237 231 CGGGCUCC G GAUCCCAG1477 CUGGGAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAGCCCG 4238 232GGGCUCCG G AUCCCAGC 1478 GCUGGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCGGAGCCC 4239 265 UGCUCUGC G GAUCUCCC 1479 GGGAGAUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCAGAGCA 4240 266 GCUCUGCG G AUCUCCCC 1480 GGGGAGAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAGAGC 4241 294 CACAGCCC G GACCCGGG1481 CCCGGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCUGUG 4242 295ACAGCCCG G ACCCGGGG 1482 CCCCGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCGGGCUGU 4243 300 CCGGACCC G GGGGCUGG 1483 CCAGCCCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGUCCGG 4244 301 CGGACCCG G GGGCUGCC 1484 GCCAGCCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGUCCG 4245 302 GCACCCGG G GGCUGGCC1485 GGCCAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGGUCC 4246 303GACCCGGG G GCUGGCCC 1486 GGGCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCCGGGUC 4247 307 CGGGGGCU G GCCCAGGG 1487 CCCUGGGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCCCCCG 4248 313 CUGGCCCA G GGCCCUGC 1488 GCAGGGCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCCAG 4249 314 UGGCCCAG G CCCCUGCA1489 UGCAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCCA 4250 323GCCCUGCA G GCCCUGGC 1490 GCCAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGCAGGGC 4251 329 CAGGCCCU G GCGUCCUG 1491 CAGGACGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGGCCUG 4252 362 UCUCCUGA G AAGCCACC 1492 GGUGGCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGAGA 4253 382 ACCACCCA G ACUUGGGG1493 CCCCAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUGGU 4254 387CCAGACUU G GGGGCAGG 1494 CCUGCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAAGUCUGG 4255 388 CAGACUUG G GGGCAGGC 1495 GCCUGCCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAAGUCUG 4256 389 AGACUUGG G GGCAGGCG 1496 CGCCUGCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAGUCU 4257 390 GACUUGGG G GCAGGCGC1497 GCGCCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAAGUC 4258 394UGGGGGCA G GCGCCAGG 1498 CCUGGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGCCCCCA 4259 401 AGGCGCCA G GGACGGAC 1499 GUCCGUCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGGCGCCU 4260 402 GGCGCCAG G GACGGACG 1500 CGUCCGUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCGCC 4261 403 GCGCCAGG G ACGGACGU1501 ACGUCCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGGCGC 4262 406CCAGGGAC G GACGUGGG 1502 CCCACGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGUCCCUGG 4263 407 CAGGGACG G ACGUGGGC 1503 GCCCACGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGUCCCUG 4264 412 ACGGACGU G GGCCAGUG 1504 CACUGGCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGUCCGU 4265 413 CGGACGUG G GCCAGUGC1505 GCACUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACGUCCG 4266 429CGAGCCCA G AGGGCCCG 1506 CGGGCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGGGCUCG 4267 431 AGCCCAGA G GGCCCGAA 1507 UUCGGGCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCUGGGCU 4268 432 GCCCAGAG G GCCCGAAG 1508 CUUCGGGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGGGC 4269 440 GGCCCGAA G GCCGGGGC1509 GCCCCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCGGGCC 4270 444CGAAGGCC G GGGCCCAC 1510 GUGGGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGCCUUCG 4271 445 GAAGGCCG G GGCCCACC 1511 GGUGGGCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGGCCUUC 4272 446 AAGGCCGG G GCCCACCA 1512 UGGUGGGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGCCUU 4273 456 CCCACCAU G GCCCAAGC1513 GCUUGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGUGGG 4274 473CCUGCCCU G GCUCCUGC 1514 GCAGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGGCAGG 4275 485 CCUGCUGU G GAUGGGCG 1515 CGCCCAUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACAGCAGG 4276 486 CUGCUGUG G AUGGGCGC 1516 GCGCCCAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGCAG 4277 489 CUGUGGAU G GGCGCGGG1517 CCCGCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCACAG 4278 490UGUGGAUG G GCGCGGGA 1518 UCCCGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCAUCCACA 4279 495 AUGGGCGC G GGAGUGCU 1519 AGCACUCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCGCCCAU 4280 496 UGGGCGCG G GAGUGCUG 1520 CAGCACUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGCCCA 4281 497 GGGCGCGG G AGUGCUGC1521 GCAGCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCGCCC 4282 514CUGCCCAC G GCACCCAG 1522 CUGGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGUGGGCAG 4283 526 CCCAGCAC G GCAUCCGG 1523 CCGGAUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GUGCUGGG 4284 533 CGGCAUCC G GCUGCCCC 1524 GGGGCAGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAUGCCG 4285 550 UGCGCAGC G GCCUGGGG1525 CCCCAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGCGCA 4286 555AGCGGCCU G GGGGGCGC 1526 GCGCCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGCCGCU 4287 556 GCGGCCUG G GGGGCGCC 1527 GGCGCCCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGGCCGC 4288 557 CGGCCUGG G GGGCGCCC 1528 GGGCGCCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGCCG 4289 558 GGCCUGGG G CGCGCCCC1529 GGGGCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGGCC 4290 559GCCUGGGG G GCGCCCCC 1530 GGGGGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCCCAGGC 4291 570 GCCCCCCU G GGGCUGCG 1531 CGCAGCCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGGGGGC 4292 571 CCCCCCUG G GGCUGCGG 1532 CCGCAGCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGGGG 4293 572 CCCCCUGG G GCUGCGGC1533 GCCGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGGGG 4294 578GGGGCUGC G GCUGCCCC 1534 GGGGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGCAGCCCC 4295 587 GCUGCCCC G GGAGACCG 1535 CGGUCUCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGGGCAGC 4296 588 CUGCCCCG G GAGACCGA 1536 UCGGUCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGGCAG 4297 589 UGCCCCGG G AGACCGAC1537 GUCGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGGGCA 4298 591CCCCGGGA G ACCGACGA 1538 UCGUCGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCCCGGGG 4299 601 CCGACGAA G AGCCCGAG 1539 CUCGGGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCGUCGG 4300 609 GAGCCCGA G GAGCCCGG 1540 CCGGGCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGGCUC 4301 610 AGCCCGAG G AGCCCGGC1541 GCCGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGGCU 4302 616AGGAGCCC G GCCGGAGG 1542 CCUCCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGGGGCUCCU 4303 620 GCCCGGCC G GAGGGGCA 1543 UGCCCCUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGCCGGGC 4304 621 CCCGGCCG G AGGGGCAG 1544 CUGCCCCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCCGGG 4305 623 CGGCCGGA G GGGCAGCU1545 AGCUGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCGGCCG 4306 624GGCCGGAG G GGCAGCUU 1546 AAGCUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCUCCGGCC 4307 625 GCCGGAGG G GCAGCUUU 1547 AAAGCUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCUCCGGC 4308 636 AGCUUUGU G GAGAUGGU 1548 ACCAUCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAAGCU 4309 637 GCUUUGUG G AGAUGGUG1549 CACCAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAAAGC 4310 639UUUGUGGA G AUGGUGGA 1550 UCCACCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCCACAAA 4311 642 GUGGAGAU G GUGGACAA 1551 UUGUCCAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUCUCCAC 4312 645 GAGAUGGU G GACAACCU 1552 AGGUUGUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAUCUC 4313 646 AGAUGGUG G ACAACCUG1553 CAGGUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCAUCU 4314 656CAACCUGA G GGGCAAGU 1554 ACUUGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCAGGUUG 4315 657 AACCUGAG G GGCAAGUC 1555 GACUUGCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUCAGGUU 4316 658 ACCUGAGG G GCAAGUCG 1556 CGACUUGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCAGGU 4317 666 GGCAAGUC G GGGCAGGG1557 CCCUGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACUUGCC 4318 667GCAAGUCG G CGCAGGGC 1558 GCCCUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCGACUUGC 4319 668 CAAGUCGG G GCAGGGCU 1559 AGCCCUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCGACUUG 4320 672 UCGGGGCA G GGCUACUA 1560 UAGUAGCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCCGA 4321 673 CGGGGCAG G GCUACUAC1561 GUAGUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCCCCG 4322 684UACUACGU G GAGAUGAC 1562 GUCAUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGACGUAGUA 4323 685 ACUACGUG G AGAUGACC 1563 GGUCAUCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACGUAGU 4324 687 UACGUGGA G AUGACCGU 1564 ACGGUCAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCACGUA 4325 696 AUGACCGU G GGCAGCCC1565 GGGCUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGGUCAU 4326 697UGACCGUG G GCAGCCCC 1566 GGGGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCACGGUCA 4327 711 CCCCCGCA G ACGCUCAA 1567 UUGAGCGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGCGGGGG 4328 726 AACAUCCU G GUGGAUAC 1568 GUAUCCACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAUGUU 4329 729 AUCCUGGU G GAUACAGG1569 CCUGUAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAGGAU 4330 730UCCUGGUG G AUACAGGC 1570 GCCUGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCACCAGGA 4331 736 UGGAUACA G GCAGCAGU 1571 ACUGCUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGUAUCCA 4332 756 UUUGCAGU G GGUGCUGC 1572 GCAGCACCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGCAAA 4333 757 UUGCAGUG G GUGCUGCC1573 GGCAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUGCAA 4334 795UACUACCA G AGGCAGCU 1574 AGCUGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUGGUAGUA 4335 797 CUACCAGA G GCAGCUGU 1575 ACAGCUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCUGGUAG 4336 818 CACAUACC G GGACCUCC 1576 GGAGGUCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUAUGUG 4337 819 ACAUACCG G GACCUCCG1577 CGGAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUAUGU 4338 820CAUACCGG G ACCUCCGG 1578 CCGGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCGGUAUG 4339 827 GGACCUCC G GAAGGGUG 1579 CACCCUUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGAGGUCC 4340 828 GACCUCCG G AAGGGUGU 1580 ACACCCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGAGGUC 4341 831 CUCCGGAA G GGUGUGUA1581 UACACACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCGGAG 4342 832UCCGGAAG G GUGUGUAU 1582 AUACACAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCUUCCGGA 4343 855 UACACCCA G GGCAAGUG 1583 CACUUGCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGGGUGUA 4344 856 ACACCCAG G GCAAGUGG 1584 CCACUUGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGUGU 4345 863 GGGCAAGU G GGAAGGGG1585 CCCCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGCCC 4346 864GGCAAGUG G GAAGGGGA 1586 UCCCCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCACUUGCC 4347 865 GCAAGUGG G AAGGGGAG 1587 CUCCCCUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCACUUGC 4348 868 AGUGGGAA G GGGAGCUG 1588 CAGCUCCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCACU 4349 869 GUGGGAAG G GGAGCUGG1589 CCAGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCCCAC 4350 870UGGGAAGG G GAGCUGGG 1590 CCCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGCCUUCCCA 4351 871 GGGAAGGG G AGCUGGGC 1591 GCCCAGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCCUUCCC 4352 876 GGGGAGCU G GGCACCGA 1592 UCGGUGCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCCC 4353 877 GGGAGCUG G GCACCGAC1593 GUCGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUCCC 4354 888ACCGACCU G GUAAGCAU 1594 AUGCUUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGUCGGU 4355 904 UCCCCCAU G GCCCCAAC 1595 GUUGGGGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUGGGGGA 4356 952 CUGAAUCA G ACAAGUUC 1596 GAACUUGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUUCAG 4357 970 UCAUCAAC G GCUCCAAC1597 GUUGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUGAUGA 4358 980CUCCAACU G GGAAGGCA 1598 UGCCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGUUGGAG 4359 981 UCCAACUG G GAAGGCAU 1599 AUGCCUUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGUUGGA 4360 982 CCAACUGG G AAGGCAUC 1600 GAUGCCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUUGG 4361 985 ACUGGGAA G GCAUCCUG1601 CAGGAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCAGU 4362 993GGCAUCCU G GGGCUGGC 1602 GCCAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGAGGAUGCC 4363 994 GCAUCCUG G GGCUGGCC 1603 GGCCAGCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGGAUGC 4364 995 CAUCCUGG G GCUGGCCU 1604 AGGCCAGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGAUG 4365 999 CUGGGGCU G GCCUAUGC1605 GCAUAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCCAG 4366 1011UAUGCUGA G AUUGCCAG 1606 CUGGCAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGGUCAGCAUA 4367 1019 GAUUGCCA G GCCUGACG 1607 CGUCAGGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGGCAAUC 4368 1035 GACUCCCU G GAGCCUUU 1608 AAAGGCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGAGUC 4369 1036 ACUCCCUG GAGCCUUUC 1609 GAAAGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGAGU 43701056 GACUCUCU G GUAAAGCA 1610 UGCUUUAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGAGAGUC 4371 1065 GUAAAGCA G ACCCACGU 1611 ACGUGGGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUUUAC 4372 1102 AGCUUUGU GGUGCUGGC 1612 GCCAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAAGCU 43731108 GUGGUGCU G GCUUCCCC 1613 GGGGAAGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCACCAC 4374 1137 GAAGUGCU G GCCUCUGU 1614 ACAGAGGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACUUC 4375 1147 CCUCUGUC GGAGGCAGC 1615 GCUCCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACAGAGG 43761148 CUCUGUCG G AGGGAGCA 1616 UGCUCCCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGACAGAG 4377 1150 CUGUCGGA G GGAGCAUG 1617 CAUGCUCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCGACAG 4378 1151 UGUCGGAG GGAGCAUGA 1618 UCAUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCGACA 43791152 GUCGGAGG G AGCAUGAU 1619 AUCAUGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCUCCGAC 4380 1165 UGAUCAUU G GAGGUAUC 1620 GAUACCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGAUCA 4381 1166 GAUCAUUG GAGGUAUCG 1621 CGAUACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUGAUC 43821168 UCAUUGGA G GUAUCGAC 1622 GUCGAUAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCCAAUGA 4383 1192 UGUACACA G GCAGUCUC 1623 GAGACUGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGUACA 4384 1202 CAGUCUCU GGUAUACAC 1624 GUGUAUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGACUG 43851217 ACCCAUCC G GCGGGAGU 1625 ACUCCCGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GGAUGGGU 4386 1220 CAUCCGGC G GGAGUGGU 1626 ACCACUCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGGAUG 4387 1221 AUCCGGCG GGAGUGGUA 1627 UACCACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGGAU 43881222 UCCGGCGG G AGUGGUAU 1628 AUACCACU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCGCCGGA 4389 1226 GCGGGAGU G GUAUUAUG 1629 CAUAAUACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCCCGC 4390 1236 UAUUAUGA GGUGAUCAU 1630 AUGAUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUAAUA 43911250 CAUUGUGC G GGUGGAGA 1631 UCUCCACC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCACAAUG 4392 1251 AUUGUGCG G GUGGAGAU 1632 AUCUCCACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCACAAU 4393 1254 GUGCGGGU GGAGAUCAA 1633 UUGAUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCGCAC 43941255 UGCGGGUG G AGAUCAAU 1634 AUUGAUCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACCCGCA 4395 1257 CGGGUGGA G AUCAAUGG 1635 CCAUUGAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCACCCG 4396 1264 ACAUCAAU GGACAGGAU 1636 AUCCUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGAUCU 43971265 GAUCAAUG G ACAGGAUC 1637 GAUCCUGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAUUGAUC 4398 1269 AAUGGACA G GAUCUGAA 1638 UUCAGAUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCCAUU 4399 1270 AUGGACAG GAUCUGAAA 1639 UUUCAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUCCAU 44001281 CUGAAAAU G GACUGCAA 1640 UUGCAGUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUUUUCAG 4401 1282 UGAAAAUG G ACUGCAAG 1641 CUUGCAGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUUUCA 4402 1290 GACUGCAA GGAGUACAA 1642 UUGUACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCAGUC 44031291 ACUGCAAG G AGUACAAC 1643 GUUGUACU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUUGCAGU 4404 1308 UAUGACAA G AGCAUUGU 1644 ACAAUGCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUCAUA 4405 1317 AGCAUUGU GGACAGUGG 1645 CCACUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAUGCU 44061318 GCAUUGUG G ACAGUGGC 1646 GCCACUGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACAAUGC 4407 1324 UGGACAGU G GCACCACC 1647 GGUGGUGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUCCA 4408 1350 UUGCCCAA GAAAGUGUU 1648 AACACUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGCAA 44091383 UCCAUCAA G GCAGCCUC 1649 GAGGCUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUGAUGGA 4410 1398 UCCUCCAC G GAGAAGUU 1650 AACUUCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGAGGA 4411 1399 CCUCCACG GAGAAGUUC 1651 GAACUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUGGAGG 44121401 UCCACGGA G AAGUUCCC 1652 GGGAACUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCCGUGGA 4413 1414 UCCCUGAU G GUUUCUGG 1653 CCAGAAACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGGGA 4414 1421 UGGUUUCU GGCUAGGAG 1654 CUCCUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAACCA 44151426 UCUGGCUA G GAGAGCAG 1655 CUGCUCUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UAGCCAGA 4416 1427 CUGGCUAG G AGAGCAGC 1656 GCUGCUCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAGCCAG 4417 1429 GGCUAGGA GACCAGCUG 1657 CAGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUAGCC 44181437 GAGCAGCU G GUGUGCUG 1658 CAGCACAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCUGCUC 4419 1445 GGUGUGCU G GCAAGCAG 1659 CUGCUUGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACACC 4420 1453 GGCAAGCA GGCACCACC 1660 GGUGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUUGCC 44211466 CACCCCUU G GAACAUUU 1661 AAAUGUUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAGGGGUG 4422 1467 ACCCCUUG G AACAUUUU 1662 AAAAUGUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGGGGU 4423 1500 UACCUAAU GGGUGAGGU 1663 ACCUCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAGGUA 44241501 ACCUAAUG G GUGAGGUU 1664 AACCUCAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAUUAGGU 4425 1506 AUGGGUGA G GUUACCAA 1665 UUGGUAACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACCCAU 4426 1556 AUACCUGC GGCCAGUGG 1666 CCACUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGGUAU 44271563 CGGCCAGU G GAAGAUGU 1667 ACAUCUUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACUGGCCG 4428 1564 GGCCAGUG G AAGAUGUG 1668 CACAUCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUGGCC 4429 1567 CAGUGGAA GAUGUGGCC 1669 GGCCACAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCACUG 44301572 GAAGAUGU G GCCACGUC 1670 GACGUGGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACAUCUUC 4431 1585 CGUCCCAA G ACGACUGU 1671 ACAGUCGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGACG 4432 1623 UCAUCCAC GGGCACUGU 1672 ACAGUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGAUGA 44331624 CAUCCACG G GCACUGUU 1673 AACAGUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGUGGAUG 4434 1635 ACUGUUAU G GGAGCUGU 1674 ACAGCUCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAACAGU 4435 1636 CUGUUAUG GGAGCUGUU 1675 AACAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUAACAG 44361637 UGUUAUGG G AGCUGUUA 1676 UAACAGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCAUAACA 4437 1650 GUUAUCAU G GAGGGCUU 1677 AAGCCCUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAUAAC 4438 1651 UUAUCAUG GAGGGCUUC 1678 GAAGCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGAUAA 44391653 AUCAUGGA G GGCUUCUA 1679 UAGAAGCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCCAUGAU 4440 1654 UCAUGGAG G GCUUCUAC 1680 GUAGAAGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAUGA 4441 1676 CUUUGAUC GGGCCCGAA 1681 UUCGGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUCAAAG 44421677 UUUGAUCG G GCCCGAAA 1682 UUUCGGGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CGAUCAAA 4443 1693 AACGAAUU G GCUUUGCU 1683 AGCAAAGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUCGUU 4444 1733 UGAGUUCA GGACGGCAG 1684 CUGCCGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAACUCA 44451734 GAGUUCAG G ACGGCAGC 1685 GCUGCCGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUGAACUC 4446 1737 UUCAGGAC G GCAGCGGU 1686 ACCGCUGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCCUGAA 4447 1743 ACGGCAGC GGUGGAAGG 1687 CCUUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGCCGU 44481746 GCAGCGGU G GAAGGCCC 1688 GGGCCUUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG ACCGCUGC 4449 1747 CAGCGGUG G AAGGCCCU 1689 AGGGCCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCGCUG 4450 1750 CGGUGGAA GGCCCUUUU 1690 AAAAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCACCG 44511767 GUCACCUU G GACAUGGA 1691 UCCAUGUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAGGUGAC 4452 1768 UCACCUUG G ACAUGGAA 1692 UUCCAUGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGGUGA 4453 1773 UUGGACAU GGAAGACUG 1693 CAGUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUCCAA 44541774 UGGACAUG G AAGACUGU 1694 ACAGUCUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAUGUCCA 4455 1777 ACAUGGAA G ACUGUGGC 1695 GCCACAGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCAUGU 4456 1783 AAGACUGU GGCUACAAC 1696 GUUGUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUCUU 44571800 AUUCCACA G ACAGAUGA 1697 UCAUCUGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGUGGAAU 4458 1804 CACAGACA G AUGAGUCA 1698 UGACUCAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCUGUG 4459 1839 UAUGUCAU GGCUGCCAU 1699 AUGGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGACAUA 44601881 UGCCUCAU G GUGUGUCA 1700 UGACACAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUGAGGCA 4461 1892 GUGUCAGU G GCGCUGCC 1701 GGCAGCGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGACAC 4462 1960 UGAAGUGA GGAGGCCCA 1702 UGGGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACUUCA 44631961 GAAGUGAG G AGGCCCAU 1703 AUGGGCCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CUCACUUC 4464 1963 AGUGAGGA G GCCCAUGG 1704 CCAUGGGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCACU 4465 1970 AGGCCCAU GGGCAGAAG 1705 CUUCUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGGCCU 44661971 GGCCCAUG G GCAGAAGA 1706 UCUUCUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAUGGGCC 4467 1975 CAUGGGCA G AAGAUAGA 1707 UCUAUCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCAUG 4468 1978 GGGCAGAA GAUAGAGAU 1708 AUCUCUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGCCC 44691982 AGAAGAUA G AGAUUCCC 1709 GGGAAUCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UAUCUUCU 4470 1984 AAGAUAGA G AUUCCCCU 1710 AGGGGAAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUAUCUU 4471 1993 AUUCCCCU GGACCACAC 1711 GUGUGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGAAU 44721994 UUCCCCUG G ACCACACC 1712 GGUGUGGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CAGGGGAA 4473 2008 ACCUCCGU G GUUCACUU 1713 AAGUGAACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGGAGGU 4474 2018 UUCACUUU GGUCACAAG 1714 CUUGUGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGUGAA 44752029 CACAAGUA G GAGACACA 1715 UGUGUCUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UACUUGUG 4476 2030 ACAAGUAG G AGACACAG 1716 CUGUGUCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUACUUGU 4477 2032 AAGUAGGA GACACAGAU 1717 AUCUGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUACUU 44782038 GAGACACA G AUGGCACC 1718 GGUGCCAU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGUGUCUC 4479 2041 ACACAGAU G GCACCUGU 1719 ACAGGUGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUGUGU 4480 2050 GCACCUGU GGCCAGAGC 1720 GCUCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGGUGC 44812055 UGUGGCCA G AGCACCUC 1721 GAGGUGCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGGCCACA 4482 2065 GCACCUCA G GACCCUCC 1722 GGAGGGUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGUGC 4483 2066 CACCUCAG GACCCUCCC 1723 GGGAGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAGGUG 44842101 GCCUUGAU G GAGAAGGA 1724 UCCUUCUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AUCAAGGC 4485 2102 CCUUGAUG G AGAAGGAA 1725 UUCCUUCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAAGG 4486 2104 UUGAUGGA GAAGGAAAA 1726 UUUUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAUCAA 44872107 AUGGAGAA G GAAAAGGC 1727 GCCUUUUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCUCCAU 4488 2108 UGGAGAAG G AAAAGGCU 1728 AGCCUUUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUCCA 4489 2113 AAGGAAAA GGCUGGCAA 1729 UUGCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUCCUU 44902117 AAAAGGCU G GCAAGGUG 1730 CACCUUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGCCUUUU 4491 2122 GCUGGCAA G GUGGGUUC 1731 GAACCCACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCCAGC 4492 2125 GGCAAGGU GGGUUCCAG 1732 CUGGAACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUUGCC 44932126 GCAAGGUG G GUUCCAGG 1733 CCUGGAAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CACCUUGC 4494 2133 GGGUUCCA G GGACUGUA 1734 UACAGUCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAACCC 4495 2134 GGUUCCAG GGACUGUAC 1735 GUACAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGAACC 44962135 GUUCCAGG G ACUGUACC 1736 GGUACAGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCUGGAAC 4497 2148 UACCUGUA G GAAACAGA 1737 UCUGUUUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACAGGUA 4498 2149 ACCUGUAG GAAACAGAA 1738 UUCUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUACAGGU 44992155 AGGAAACA G AAAAGAGA 1739 UCUCUUUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGUUUCCU 4500 2160 ACAGAAAA G AGAAGAAA 1740 UUUCUUCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUCUGU 4501 2162 AGAAAAGA GAAGAAAGA 1741 UCUUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUUUCU 45022165 AAAGAGAA G AAAGAAGC 1742 GCUUCUUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCUCUUU 4503 2169 AGAAGAAA G AAGCACUC 1743 GAGUGCUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCUUCU 4504 2182 ACUCUGCU GGCGGGAAU 1744 AUUCCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGAGU 45052185 CUGCUGGC G GGAAUACU 1745 AGUAUUCC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG GCCAGCAG 4506 2186 UGCUGGCG G GAAUACUC 1746 CAGUAUUCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCAGCA 4507 2187 GCUGGCGG GAAUACUCU 1747 ACAGUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCCAGC 45082197 AUACUCUU G GUCACCUC 1748 GAGGUGAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AAGAGUAU 4509 2217 UUUAAGUC G GGAAAUUC 1749 GAAUUUCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACUUAAA 4510 2218 UUAAGUCG GGAAAUUCU 1750 AGAAUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGACUUAA 45112219 UAAGUCGG G AAAUUCUG 1751 CAGAAUUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCGACUUA 4512 2311 UAGUUUCA G AAGUACUG 1752 CAGUACUUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAACUA 4513 2319 GAAGUACU GGCAUCACA 1753 UGUGAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUACUUC 45142332 CACACGCA G GUUACCUU 1754 AAGGUAAC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UGCGUGUG 4515 2341 GUUACCUU G GCGUGUGU 1755 ACACACGCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGUAAC 4516 2356 GUCCCUGU GGUACCCUG 1756 CAGGGUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGGGAC 45172364 GGUACCCU G GCAGAGAA 1757 UUCUCUGC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG AGGGUACC 4518 2368 CCCUGGCA G AGAAGAGA 1758 UCUCUUCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCAGGG 4519 2370 CUGGCAGA GAAGAGACC 1759 GGUCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGCCAG 45202373 GCAGAGAA G AGACCAAG 1760 CUUGGUCU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UUCUCUGC 4521 2375 AGAGAAGA G ACCAAGCU 1761 AGCUUGGUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCUCU 4522 2396 UCCCUGCU GGCCAAAGU 1762 ACUUUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGGGA 45232410 AGUCAGUA G GAGAGGAU 1763 AUCCUCUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UACUGACU 4524 2411 GUCAGUAG G AGAGGAUG 1764 CAUCCUCUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUACUGAC 4525 2413 CAGUAGGA GAGGAUGCA 1765 UGCAUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUACUG 45262415 GUAGGAGA G GAUGCACA 1766 UGUGCAUC GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCUCCUAC 4527 2416 UAGGAGAG G AUGCACAG 1767 CUGUGCAUGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUCCUA 4528 2441 UUGCUUUA GAGACAGGG 1768 CCCUGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAAGCAA 45292443 GCUUUAGA G ACAGGGAC 1769 GUCCCUGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UCUAAAGC 4530 2447 UAGAGACA G GGACUGUA 1770 UACAGUCCGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCUCUA 4531 2448 AGAGACAG GGACUGUAU 1771 AUACAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUCUCU 45322449 GAGACAGG G ACUGUAUA 1772 UAUACAGU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG CCUGUCUC 4533 2473 CUAACAUU G GUGCAAAG 1773 CUUUGCACGGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGUUAG 4534 2481 GGUGCAAA GAUUGCCUC 1774 GAGGCAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGCACC 45352511 AAAAACUA G AAAAAAAA 1775 UUUUUUUU GGAGGAAACUCC CUUCAAGGACAUCGUCCGGG UAGUUUUU 4536

[0310] All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

[0311] One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described herein as presently representative ofpreferred embodiments are exemplary and are not intended as limitationson the scope of the invention. Changes therein and other uses will occurto those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope of the claims.

[0312] It will be readily apparent to one skilled in the art thatvarying substitutions and modifications may be made to the inventiondisclosed herein without departing from the scope and spirit of theinvention. Thus, such additional embodiments are within the scope of thepresent invention and the following claims.

[0313] The invention illustratively described herein suitably may bepracticed in the absence of any element or elements, limitation orlimitations which is not specifically disclosed herein. Thus, forexample, in each instance herein any of the terms “comprising”,“consisting essentially of” and “consisting of” may be replaced witheither of the other two terms. The terms and expressions which have beenemployed are used as terms of description and not of limitation, andthere is no intention that in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments, optional features, modification andvariation of the concepts herein disclosed may be resorted to by thoseskilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention as defined by thedescription and the appended claims.

[0314] In addition, where features or aspects of the invention aredescribed in terms of Markush groups or other grouping of alternatives,those skilled in the art will recognize that the invention is alsothereby described in terms of any individual member or subgroup ofmembers of Markush group or other group.

[0315] Other embodiments are within the following claims.

What we claim is:
 1. A nucleic acid sensor molecule which modulatesexpression of a beta site APP-cleaving enzyme (BACE) gene.
 2. A nucleicacid sensor molecule which modulates expression of a presenilin (ps-2)gene.
 3. A nucleic acid sensor molecule which modulates expression of anamyloid precursor protein (APP) gene.
 4. The nucleic acid sensormolecule of any of claims 1-3, wherein said nucleic acid sensor moleculeis adapted for use to treat Alzheimer's disease.
 5. The nucleic acidsensor molecule of claim 1, wherein said nucleic acid sensor moleculehas an endonuclease activity to cleave RNA encoded by said BACE gene. 6.The nucleic acid sensor molecule of claim 2, wherein said nucleic acidsensor molecule has an endonuclease activity to cleave RNA encoded bysaid ps-2 gene.
 7. The nucleic acid sensor molecule of claim 3, whereinsaid nucleic acid sensor molecule has an endonuclease activity to cleaveRNA encoded by said APP gene.
 8. The nucleic acid sensor molecule ofclaim 1, wherein a binding arm of the nucleic acid sensor moleculecomprise sequences complementary to any of sequences having SEQ ID NOs:1-1775.
 9. The nucleic acid sensor molecule of claim 1, wherein anenzymatic nucleic acid portion of the nucleic acid sensor moleculecomprises any of sequences having SEQ ID NOs: 1776-3972.
 10. The nucleicacid sensor molecule of any of claims 1-3, wherein said nucleic acidsensor molecule comprises a hammerhead enzymatic nucleic acid motif. 11.The nucleic acid sensor molecule of any of claims 1-3, wherein saidnucleic acid sensor molecule comprises an Inozyme enzymatic nucleic acidmotif.
 12. The nucleic acid sensor molecule of any of claims 1-3,wherein said nucleic acid sensor molecule comprises a Zinzyme enzymaticnucleic acid motif.
 13. The nucleic acid sensor molecule of any ofclaims 1-3, wherein said nucleic acid sensor molecule comprises anAmberzyme enzymatic nucleic acid motif.
 14. The nucleic acid sensormolecule of any of claims 1-3, wherein said nucleic acid sensor moleculecomprises a G-cleaver enzymatic nucleic acid motif.
 15. The nucleic acidsensor molecule of any of claims 1-3, wherein said nucleic acid sensormolecule comprises a hairpin enzymatic nucleic acid motif.
 16. Thenucleic acid sensor molecule of any of claims 1-3, wherein said nucleicacid sensor molecule comprises a DNAzyme.
 17. The nucleic acid sensormolecule of claim 1, wherein said nucleic acid sensor molecule comprisesbetween 12 and 100 bases complementary to RNA of a BACE gene.
 18. Thenucleic acid sensor molecule of claim 1, wherein said nucleic acidsensor molecule comprises between 14 and 24 bases complementary toRNA ofa BACE gene.
 19. The nucleic acid sensor molecule of claim 2, whereinsaid nucleic acid sensor molecule comprises between 12 and 100 basescomplementary to RNA of a ps-2 gene.
 20. The nucleic acid sensormolecule of claim 2, wherein said nucleic acid sensor molecule comprisesbetween 14 and 24 bases complementary to RNA of a ps-2 gene.
 21. Thenucleic acid sensor molecule of claim 3, wherein said nucleic acidsensor molecule comprises between 12 and 100 bases complementary to RNAof a APP gene.
 22. The nucleic acid sensor molecule of claim 3, whereinsaid nucleic acid sensor molecule comprises between 14 and 24 basescomplementary to RNA of an APP gene.
 23. The nucleic acid sensormolecule of any of claims 1-3, wherein said nucleic acid sensor moleculeis chemically synthesized.
 24. The nucleic acid sensor molecule of anyof claims 1-3, wherein said nucleic acid sensor molecule comprises atleast one 2′-sugar modification.
 25. The nucleic acid sensor molecule ofany of claims 1-3, wherein said nucleic acid sensor molecule comprisesat least one nucleic acid base modification.
 26. The nucleic acid sensormolecule of any of claims 1-3, wherein said nucleic acid sensor moleculecomprises at least one phosphate backbone modification.
 27. A mammaliancell including the nucleic acid sensor molecule of any of claims 1-3.28. The mammalian cell of claim 27, wherein said mammalian cell is ahuman cell.
 29. A method of reducing BACE activity in a cell, comprisingcontacting said cell with the nucleic acid sensor molecule of claim 1,under conditions suitable for said inhibition.
 30. A method of treatmentof a patient having a condition associated with the level of BACE,comprising contacting cells of said patient with the nucleic acid sensormolecule of claim 1, under conditions suitable for said treatment. 31.The method of claim 30 further comprising the use of one or more drugtherapies under conditions suitable for said treatment.
 32. A method ofcleaving RNA of a BACE gene, comprising, contacting the nucleic acidsensor molecule of claim 1, with said RNA under conditions suitable forthe cleavage of said RNA.
 33. The method of claim 32, wherein saidcleavage is carried out in the presence of a divalent cation.
 34. Themethod of claim 33, wherein said divalent cation is Mg²⁺.
 35. Thenucleic acid sensor molecule of any of claims 1-3, wherein said nucleicacid sensor molecule comprises a cap structure, wherein the capstructure is at the 5′-end or 3′-end or both the 5′-end and the 3′-end.36. A method for treatment of Alzheimer's disease comprisingadministering to a patient the nucleic acid sensor molecule of any ofclaims 1-3 under conditions suitable for said treatment.
 37. The methodof claim 36, wherein said method further comprises administering to saidpatient the enzymatic nucleic acid molecule in conjunction with one ormore of other therapies.
 38. A nucleic acid sensor molecule capable ofmodulating the expression of BACE in the presence of beta-amyloidprotein.
 39. A nucleic acid sensor molecule capable of modulating theexpression of presenilin-2 in the presence of beta-amyloid protein. 40.A nucleic acid sensor molecule capable of modulating the expression ofamyloid precursor protein in the presence of beta-amyloid protein.
 41. Anucleic acid sensor molecule capable of modulating the expression ofBACE in the presence of amyloid precursor protein.
 42. A nucleic acidsensor molecule capable of modulating the expression of presenilin-2 inthe presence of amyloid precursor protein.
 43. A nucleic acid sensormolecule capable of modulating the expression of amyloid precursorprotein in the presence of amyloid precursor protein.
 44. A nucleic acidsensor molecule capable of modulating the expression of BACE in thepresence of BACE RNA.
 45. A nucleic acid sensor molecule capable ofmodulating the expression of presenilin-2 in the presence of BACE RNA.46. A nucleic acid sensor molecule capable of modulating the expressionof amyloid precursor protein in the presence of BACE RNA.
 47. A nucleicacid sensor molecule capable of modulating the expression of BACE, inthe presence of presenilin-2 RNA.
 48. A nucleic acid sensor moleculecapable of modulating the expression of presenilin-2 in the presence ofpresenilin-2 RNA.
 49. A nucleic acid sensor molecule capable ofmodulating the expression of amyloid precursor protein in the presenceof presenilin-2 RNA.
 50. A nucleic acid sensor molecule capable ofmodulating the expression of BACE in the presence of amyloid precursorprotein RNA.
 51. A nucleic acid sensor molecule capable of modulatingthe expression of presenilin-2 in the presence of amyloid precursorprotein RNA.
 52. A nucleic acid sensor molecule capable of modulatingthe expression of amyloid precursor protein in the presence of amyloidprecursor protein RNA.
 53. The nucleic acid sensor molecule of any ofclaims 1-3, wherein said modulation is inhibition.
 54. The nucleic acidsensor molecule of any of claims 38-53, wherein said modulation isinhibition.